Research

15 pages, 2974 KiB

Open AccessArticle

Identification of Potential Protein Targets in Extracellular Vesicles Isolated from Chemotherapy-Treated Ovarian Cancer Cells

by Chia-Yi Chan, Yi-Chun Ni, Hieu Duc Nguyen, Yung-Fu Wu and Kuen-Haur Lee

Curr. Issues Mol. Biol. 2023, 45(9), 7417-7431; https://doi.org/10.3390/cimb45090469 - 11 Sep 2023

Cited by 1 | Viewed by 1418

Abstract

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. [...] Read more.

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. However, more than 70% of patients experience recurrence and eventually develop chemoresistance. To improve clinical outcomes in patients with ovarian cancer, novel technologies must be developed for identifying molecular alterations following drug-based treatment of ovarian cancer. Recently, extracellular vesicles (EVs) have gained prominence as the mediators of tumor progression. In this study, we used mass spectrometry to identify the changes in EV protein signatures due to different chemotherapeutic agents used for treating ovarian cancer. By examining these alterations, we identified the specific protein induction patterns of cisplatin alone, paclitaxel alone, and a combination of cisplatin and paclitaxel. Specifically, we found that drug sensitivity was correlated with the expression levels of ANXA5, CD81, and RAB5C in patients receiving cisplatin with paclitaxel. Our findings suggest that chemotherapy-induced changes in EV protein signatures are crucial for the progression of ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 4200 KiB

Open AccessArticle

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA–Gene Interaction Network Analysis

by Zhiyuan Yang, Yuanyuan Qi, Yijing Wang, Xiangyun Chen, Yuerong Wang and Xiaoli Zhang

Curr. Issues Mol. Biol. 2023, 45(9), 7374-7387; https://doi.org/10.3390/cimb45090466 - 10 Sep 2023

Cited by 1 | Viewed by 1114

Abstract

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. Methods: We [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. Methods: We performed a miRNA–gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM–DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. Results: By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term “Liver” with a statistical p-value of 1.71 × 10⁻²⁶. Function enrichment analysis indicated that these genes were significantly overrepresented in the term “monocarboxylic acid metabolic process” with a p-value = 2.94 × 10⁻¹⁸. Two sets (fourteen genes and five miRNAs) were screened by a miRNA–gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. Conclusion: We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 303 KiB

Open AccessArticle

Analysis of Genes Related to Invadopodia Formation and CTTN in Oral Squamous Cell Carcinoma—A Systematic Gene Expression Analysis

by Immanuel Desel, Susanne Jung, Nikolai Purcz, Yahya Açil, Christoph Sproll, Johannes Kleinheinz and Sonja Sielker

Curr. Issues Mol. Biol. 2023, 45(8), 6927-6940; https://doi.org/10.3390/cimb45080437 - 18 Aug 2023

Viewed by 1020

Abstract

Successful treatment for any type of carcinoma largely depends on understanding the patterns of invasion and migration. For oral squamous cell carcinoma (OSCC), these processes are not entirely understood as of now. Invadopodia and podosomes, called invadosomes, play an important role in cancer [...] Read more.

Successful treatment for any type of carcinoma largely depends on understanding the patterns of invasion and migration. For oral squamous cell carcinoma (OSCC), these processes are not entirely understood as of now. Invadopodia and podosomes, called invadosomes, play an important role in cancer cell invasion and migration. Previous research has established that cortactin (CTTN) is a major inducer of invadosome formation. However, less is known about the expression patterns of CTTN and other genes related to it or invadopodia formation in OSCC during tumor progression in particular. In this study, gene expression patterns of CTTN and various genes (n = 36) associated with invadopodia formation were analyzed to reveal relevant expression patterns and give a comprehensive overview of them. The genes were analyzed from a whole genome dataset of 83 OSCC samples relating to tumor size, grading, lymph node status, and UICC (Union for Internatioanl Cancer Control). The data revealed significant overexpression of 18 genes, most notably CTTN, SRC (SRC proto-onocogene, non-receptor tyrosine kinase), EGFR (epidermal growth factor receptor), SYK (spleen associated tyrosine kinase), WASL (WASP like actin nucleation promotion factor), and ARPC2 (arrestin beta 1) due to their significant correlation with further tumor parameters. This study is one of the first to summarize the expression patterns of CTTN and related genes in a complex group of OSCC samples. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

15 pages, 1644 KiB

Open AccessArticle

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

by Ioannis A. Voutsadakis

Curr. Issues Mol. Biol. 2023, 45(7), 6040-6054; https://doi.org/10.3390/cimb45070381 - 19 Jul 2023

Cited by 2 | Viewed by 1139

Abstract

Background: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently [...] Read more.

Background: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently not exploited in the clinic. The claudin-low phenotype is present in a subset of triple-negative breast cancers and constitutes together with basal-like cancers the most extensive groups within triple-negative breast cancers. Suppression of epithelial cell adhesion molecules in claudin-low cancers is also a hallmark of Epithelial Mesenchymal Transition (EMT). Methods: The groups of claudin-low and claudin-non-suppressed breast cancers from the extensive publicly available genomic cohorts of the METABRIC study were examined to delineate and compare their molecular landscape. Genetic and epigenetic alterations of key factors involved in EMT and potentially associated with the pathogenesis of the claudin-low phenotype were analyzed in the two groups. Results: Claudin-low cancers displayed up-regulation of several core transcription factors of EMT at the mRNA level, compared with claudin-non-suppressed breast cancers. Global promoter DNA methylation was increased in both groups of triple-negative cancers and in claudin-low ER-positive cancers compared with the rest of ER-positive cancers. Histone modifier enzymes, including methyltransferases, demethylases, acetyltransferases and deacetylases displayed amplifications more frequently in claudin-non-suppressed triple-negative cancers than in claudin-low counterparts and the expression of some of these enzymes differed significantly between the two groups. Conclusion: Claudin-low and claudin-non-suppressed triple-negative breast cancers differ in their landscape of EMT core regulators and epigenetic regulators. These differences may be explored as targets for therapeutic interventions specific to the two groups of triple-negative breast cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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13 pages, 1734 KiB

Open AccessArticle

Impact of HepG2 Cells Glutathione Depletion on Neutral Sphingomyelinases mRNA Levels and Activity

by Marie Gamal, Hatem Tallima, Hassan M. E. Azzazy and Anwar Abdelnaser

Curr. Issues Mol. Biol. 2023, 45(6), 5005-5017; https://doi.org/10.3390/cimb45060318 - 08 Jun 2023

Viewed by 1460

Abstract

Liver cancer is a prevalent form of cancer worldwide. While research has shown that increasing sphingomyelin (SM) hydrolysis by activating the cell surface membrane-associated neutral sphingomyelinase 2 (nSMase2) can control cell proliferation and apoptosis, the role of total glutathione depletion in inducing tumor [...] Read more.

Liver cancer is a prevalent form of cancer worldwide. While research has shown that increasing sphingomyelin (SM) hydrolysis by activating the cell surface membrane-associated neutral sphingomyelinase 2 (nSMase2) can control cell proliferation and apoptosis, the role of total glutathione depletion in inducing tumor cell apoptosis via nSMase2 activation is still under investigation. Conversely, glutathione-mediated inhibition of reactive oxygen species (ROS) accumulation is necessary for the enzymatic activity of nSMase1 and nSMase3, increased ceramide levels, and cell apoptosis. This study evaluated the effects of depleting total glutathione in HepG2 cells using buthionine sulfoximine (BSO). The study assessed nSMases RNA levels and activities, intracellular ceramide levels, and cell proliferation using RT-qPCR, Amplex red neutral sphingomyelinase fluorescence assay, and colorimetric assays, respectively. The results indicated a lack of nSMase2 mRNA expression in treated and untreated HepG2 cells. Depletion of total glutathione resulted in a significant increase in mRNA levels but a dramatic reduction in the enzymatic activity of nSMase1 and nSMase3, a rise in ROS levels, a decrease in intracellular levels of ceramide, and an increase in cell proliferation. These findings suggest that total glutathione depletion may exacerbate liver cancer (HCC) and not support using total glutathione-depleting agents in HCC management. It is important to note that these results are limited to HepG2 cells, and further studies are necessary to determine if these effects will also occur in other cell lines. Additional research is necessary to explore the role of total glutathione depletion in inducing tumor cell apoptosis. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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20 pages, 2935 KiB

Open AccessArticle

How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?

by Federica Nicolini, Toni Todorovski, Eduard Puig, Mireia Díaz-Lobo, Marta Vilaseca, Jesús García, David Andreu and Ernest Giralt

Curr. Issues Mol. Biol. 2023, 45(6), 4985-5004; https://doi.org/10.3390/cimb45060317 - 07 Jun 2023

Viewed by 1223

Abstract

Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 [...] Read more.

Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers, and mutations can alter the oligomeric state of the protein, having an impact on the biological function of the protein and on cell fate decisions. Here, we describe the effects of a number of representative cancer-related mutations on tetramerisation domain (TD) oligomerisation defining a peptide length that permits having a folded and structured domain, thus avoiding the effect of the flanking regions and the net charges at the N- and C-terminus. These peptides have been studied under different experimental conditions. We have applied a variety of techniques, including circular dichroism (CD), native mass spectrometry (MS) and high-field solution NMR. Native MS allows us to detect the native state of complexes maintaining the peptide complexes intact in the gas phase; the secondary and quaternary structures were analysed in solution by NMR, and the oligomeric forms were assigned by diffusion NMR experiments. A significant destabilising effect and a variable monomer population were observed for all the mutants studied. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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15 pages, 2228 KiB

Open AccessArticle

Gene Expression Profiles of Methyltransferases and Demethylases Associated with Metastasis, Tumor Invasion, CpG73 Methylation, and HPV Status in Head and Neck Squamous Cell Carcinoma

by Larisa Goričan, Tomaž Büdefeld, Helena Čelešnik, Matija Švagan, Boštjan Lanišnik and Uroš Potočnik

Curr. Issues Mol. Biol. 2023, 45(6), 4632-4646; https://doi.org/10.3390/cimb45060294 - 27 May 2023

Cited by 1 | Viewed by 1298

Abstract

Epigenetic studies on the role of DNA-modifying enzymes in HNSCC tumorigenesis have focused on a single enzyme or a group of enzymes. To acquire a more comprehensive insight into the expression profile of methyltransferases and demethylases, in the present study, we examined the [...] Read more.

Epigenetic studies on the role of DNA-modifying enzymes in HNSCC tumorigenesis have focused on a single enzyme or a group of enzymes. To acquire a more comprehensive insight into the expression profile of methyltransferases and demethylases, in the present study, we examined the mRNA expression of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, the DNA demethylases TET1, TET2, TET3, and TDG, and the RNA methyltransferase TRDMT1 by RT-qPCR in paired tumor–normal tissue samples from HNSCC patients. We characterized their expression patterns in relation to regional lymph node metastasis, invasion, HPV16 infection, and CpG73 methylation. Here, we show that tumors with regional lymph node metastases (pN+) exhibited decreased expression of DNMT1, 3A and 3B, and TET1 and 3 compared to non-metastatic tumors (pN0), suggesting that metastasis requires a distinct expression profile of DNA methyltransferases/demethylases in solid tumors. Furthermore, we identified the effect of perivascular invasion and HPV16 on DNMT3B expression in HNSCC. Finally, the expression of TET2 and TDG was inversely correlated with the hypermethylation of CpG73, which has previously been associated with poorer survival in HNSCC. Our study further confirms the importance of DNA methyltransferases and demethylases as potential prognostic biomarkers as well as molecular therapeutic targets for HNSCC. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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16 pages, 626 KiB

Open AccessArticle

Clinicopathological Characteristics and Mutational Landscape of APC, HOXB13, and KRAS among Rwandan Patients with Colorectal Cancer

by Felix Manirakiza, Eric Rutaganda, Hidetaka Yamada, Yuji Iwashita, Belson Rugwizangoga, Benoit Seminega, Vincent Dusabejambo, Gervais Ntakirutimana, Deogratias Ruhangaza, Annette Uwineza, Kazuya Shinmura and Haruhiko Sugimura

Curr. Issues Mol. Biol. 2023, 45(5), 4359-4374; https://doi.org/10.3390/cimb45050277 - 16 May 2023

Cited by 2 | Viewed by 1649

Abstract

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with [...] Read more.

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with advanced disease. Considering the paucity of oncological genetic studies in this population, we investigated the mutational status of CRC tissues, focusing on the Adenomatous polyposis coli (APC), Kirsten rat sarcoma (KRAS), and Homeobox B13 (HOXB13) genes. Our aim was to determine whether there were any differences between Rwandan patients and other populations. To do so, we performed Sanger sequencing of the DNA extracted from formalin-fixed paraffin-embedded adenocarcinoma samples from 54 patients (mean age: 60 years). Most tumors were located in the rectum (83.3%), and 92.6% of the tumors were low-grade. Most patients (70.4%) reported never smoking, and 61.1% of patients had consumed alcohol. We identified 27 variants of APC, including 3 novel mutations (c.4310_4319delAAACACCTCC, c.4463_4470delinsA, and c.4506_4507delT). All three novel mutations are classified as deleterious by MutationTaster2021. We found four synonymous variants (c.330C>A, c.366C>T, c.513T>C, and c.735G>A) of HOXB13. For KRAS, we found six variants (Asp173, Gly13Asp, Gly12Ala, Gly12Asp, Gly12Val, and Gln61His), the last four of which are pathogenic. In conclusion, here we contribute new genetic variation data and provide clinicopathological information pertinent to CRC in Rwanda. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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16 pages, 1176 KiB

Open AccessArticle

Deregulation of Autophagy and Apoptosis in Patients with Myelodysplastic Syndromes: Implications for Disease Development and Progression

by Georgia Tsekoura, Andreas Agathangelidis, Christina-Nefeli Kontandreopoulou, Angeliki Taliouraki, Georgia Mporonikola, Maria Stavropoulou, Panagiotis T. Diamantopoulos, Nora-Athina Viniou, Vassiliki Aleporou, Issidora Papassideri and Panagoula Kollia

Curr. Issues Mol. Biol. 2023, 45(5), 4135-4150; https://doi.org/10.3390/cimb45050263 - 08 May 2023

Viewed by 1310

Abstract

(1) Background: Myelodysplastic neoplasms (MDSs) consist of a group of blood malignancies with a complex biological background. In this context, we investigated the role of autophagy and apoptosis in the pathogenesis and progression of MDSs. (2) Methods: To address this issue, we performed [...] Read more.

(1) Background: Myelodysplastic neoplasms (MDSs) consist of a group of blood malignancies with a complex biological background. In this context, we investigated the role of autophagy and apoptosis in the pathogenesis and progression of MDSs. (2) Methods: To address this issue, we performed a systematic expression analysis on a total of 84 genes in patients with different types of MDSs (low/high risk of malignancy) versus healthy individuals. Furthermore, real-time quantitative PCR (qRT-PCR) was used to validate significantly upregulated or downregulated genes in a separate cohort of MDS patients and healthy controls. (3) Results: MDS patients were characterized by lower expression levels for a large series of genes involved in both processes compared to healthy individuals. Of importance, deregulation was more pronounced in patients with higher-risk MDS. Results from the qRT-PCR experiments displayed a high level of concordance with the PCR array, strengthening the relevance of our findings. (4) Conclusions: Our results indicate a clear effect of autophagy and apoptosis on MDS development, which becomes more pronounced as the disease progresses. The results from the present study are expected to assist in our understanding of the biological background of MDSs as well as in the identification of novel therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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11 pages, 762 KiB

Open AccessCommunication

The Potential Association between E2F2, MDM2 and p16 Protein Concentration and Selected Sociodemographic and Clinicopathological Characteristics of Patients with Oral Squamous Cell Carcinoma

by Agata Świętek, Karolina Gołąbek, Dorota Hudy, Jadwiga Gaździcka, Krzysztof Biernacki, Katarzyna Miśkiewicz-Orczyk, Natalia Zięba, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Curr. Issues Mol. Biol. 2023, 45(4), 3268-3278; https://doi.org/10.3390/cimb45040213 - 07 Apr 2023

Cited by 1 | Viewed by 1251

Abstract

Background: E2F transcription factor 2 (E2F2), murine double minute 2 (MDM2) and p16 are some of the key proteins associated with the control of the cell cycle. The aim of this study was to evaluate E2F2, MDM2 and p16 concentrations in the tumour [...] Read more.

Background: E2F transcription factor 2 (E2F2), murine double minute 2 (MDM2) and p16 are some of the key proteins associated with the control of the cell cycle. The aim of this study was to evaluate E2F2, MDM2 and p16 concentrations in the tumour and margin samples of oral squamous cell carcinoma and to assess their association with some selected sociodemographic and clinicopathological characteristics of the patients. Methods: The study group consisted of 73 patients. Protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results: There were no statistically significant differences in the levels of E2F2, MDM2 or p16 in the tumour samples as compared to the margin specimens. We found that patients with N0 showed significantly lower E2F2 concentrations than patients with N1 in the tumour samples and the median protein concentration of E2F2 was higher in HPV-negative patients in the tumour samples. Moreover, the level of p16 in the margin samples was lower in alcohol drinkers as compared to non-drinkers. Similar observations were found in concurrent drinkers and smokers compared to non-drinkers and non-smokers. Conclusions: E2F2 could potentially promote tumour progression and metastasis. Moreover, our results showed a differential level of the analysed proteins in response to alcohol consumption and the HPV status. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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13 pages, 1653 KiB

Open AccessArticle

Inhibitory Effect of Phosphorothioate Oligonucleotide Complementary to G6PD mRNA on Murine Melanoma

by Kseniya A. Yurchenko, Kateryna V. Laikova, Ilya O. Golovkin, Ilya A. Novikov, Alyona A. Yurchenko, Tatyana P. Makalish and Volodymyr V. Oberemok

Curr. Issues Mol. Biol. 2023, 45(4), 3180-3192; https://doi.org/10.3390/cimb45040207 - 06 Apr 2023

Viewed by 1660

Abstract

In terms of the incidence among all tumors, skin cancer is on top, with the most deadly among them being melanoma. The search for new therapeutic agents to combat melanoma is very relevant. In our opinion, antisense oligonucleotides (ASO) aimed at suppressing the [...] Read more.

In terms of the incidence among all tumors, skin cancer is on top, with the most deadly among them being melanoma. The search for new therapeutic agents to combat melanoma is very relevant. In our opinion, antisense oligonucleotides (ASO) aimed at suppressing the genes responsible for their viability in cancer cells give hope for treatment, which makes it possible to eliminate cancer cells near the tumor site both before and after surgery. In this article, we describe how Skeen-11 phosphorothioate oligonucleotide significantly decreased the proliferative activity of murine melanoma cells. Injections of Skeen-11 also inhibited tumor growth in mice with inoculated melanoma. A toxicity study showed no side effects with dose adjustments. The results show that the use of ASO Skeen-11 in vivo reduced the tumor size within 7 days, reduced the number of mitoses in the tumor cells, and increased the amount of necrosis compared with the control group. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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10 pages, 1405 KiB

Open AccessArticle

Megalin Expression in Primary Oral Squamous Cell Carcinoma Is Associated with the Presence of Lymph Node Metastases, Vascular Invasion, and Lower Overall Survival

by Ana Zulijani, Ana Milardović, Zoran Kovač, Berislav Perić and Hrvoje Jakovac

Curr. Issues Mol. Biol. 2023, 45(4), 2757-2766; https://doi.org/10.3390/cimb45040180 - 24 Mar 2023

Viewed by 947

Abstract

Megalin (LRP2) is a rapidly recycling multiligand endocytic receptor primarily expressed in polarized epithelial cells. Although megalin might be involved in tumor growth and invasiveness through several mechanisms, its role has been understudied in the field of molecular oncology so far. The present [...] Read more.

Megalin (LRP2) is a rapidly recycling multiligand endocytic receptor primarily expressed in polarized epithelial cells. Although megalin might be involved in tumor growth and invasiveness through several mechanisms, its role has been understudied in the field of molecular oncology so far. The present study aimed to evaluate the impact of megalin expression in oral squamous cell carcinoma (OSCC) on disease progression. Megalin expression was evaluated immunohistochemically in 63 OSCC specimens. Data obtained were retrospectively compared with patient clinicopathological features and their survival. The proportion of megalin-expressing cells in the primary OSCC tissue was significantly associated with metastatic spreading to lymph nodes, vascular invasion and lower overall survival rate. Results obtained by the study suggest that megalin can be considered as a novel molecule involved in OSCC pathogenesis, but also useful as a potential biomarker for cancer progression. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 1978 KiB

Open AccessArticle

Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model

by Matthieu Ferragu, Luisa Vergori, Vincent Le Corre, Sarah Bellal, Maria del Carmen Martinez and Pierre Bigot

Curr. Issues Mol. Biol. 2023, 45(3), 2491-2504; https://doi.org/10.3390/cimb45030163 - 17 Mar 2023

Viewed by 1646

Abstract

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In [...] Read more.

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients’ nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 3009 KiB

Open AccessArticle

Development of a Novel Anti-CD44 Variant 4 Monoclonal Antibody C₄₄Mab-108 for Immunohistochemistry

by Hiroyuki Suzuki, Tomohiro Tanaka, Nohara Goto, Mika K. Kaneko and Yukinari Kato

Curr. Issues Mol. Biol. 2023, 45(3), 1875-1888; https://doi.org/10.3390/cimb45030121 - 25 Feb 2023

Cited by 6 | Viewed by 2205

Abstract

CD44 has been known as a marker of tumor-initiating cells, and plays pro-tumorigenic functions in many cancers. The splicing variants play critical roles in the malignant progression of cancers by promoting stemness, cancer cell invasion or metastasis, and resistance to chemo- and radiotherapy. [...] Read more.

CD44 has been known as a marker of tumor-initiating cells, and plays pro-tumorigenic functions in many cancers. The splicing variants play critical roles in the malignant progression of cancers by promoting stemness, cancer cell invasion or metastasis, and resistance to chemo- and radiotherapy. To understand each CD44 variant (CD44v) function is essential to know the property of cancers and the establishment of the therapy. However, the function of the variant 4-encoded region has not been elucidated. Therefore, specific monoclonal antibodies (mAbs) against variant 4 are indispensable for basic research, tumor diagnosis, and therapy. In this study, we established anti-CD44 variant 4 (CD44v4) mAbs by immunizing mice with a peptide containing the variant 4-encoded region. We next performed flow cytometry, western blotting, and immunohistochemistry to characterize them. One of the established clones (C₄₄Mab-108; IgG₁, kappa) reacted with CD44v3-10-overexpressed Chinese hamster ovary-K1 cells (CHO/CD44v3-10). The K_D of C₄₄Mab-108 for CHO/CD44 v3-10 was 3.4 × 10⁻⁷ M. In western blot analysis, C₄₄Mab-108 detected CD44v3-10 in the lysate of CHO/CD44v3-10 cells. Furthermore, C₄₄Mab-108 stained formalin-fixed paraffin-embedded (FFPE) oral squamous carcinoma tissues in immunohistochemistry. These results indicated that C₄₄Mab-108 is useful to detect CD44v4 in immunohistochemistry using FFPE tissues. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 2019 KiB

Open AccessArticle

The Effect of Different Anesthetic Techniques on Proliferation, Apoptosis, and Gene Expression in Colon Cancer Cells: A Pilot In Vitro Study

by Alexandru Leonard Alexa, Ancuta Jurj, Ciprian Tomuleasa, Adrian Bogdan Tigu, Raluca-Miorita Hategan and Daniela Ionescu

Curr. Issues Mol. Biol. 2023, 45(1), 738-751; https://doi.org/10.3390/cimb45010049 - 14 Jan 2023

Cited by 2 | Viewed by 1844

Abstract

Background: Colorectal cancer is highly common and causes high mortality rates. Treatment for colorectal cancer is multidisciplinary, but in most cases the main option remains surgery. Intriguingly, in recent years, a number of studies have shown that a patient’s postoperative outcome may be [...] Read more.

Background: Colorectal cancer is highly common and causes high mortality rates. Treatment for colorectal cancer is multidisciplinary, but in most cases the main option remains surgery. Intriguingly, in recent years, a number of studies have shown that a patient’s postoperative outcome may be influenced by certain anesthetic drugs. Our main objective was to compare the effect of propofol–total intravenous anesthesia (TIVA) with sevoflurane anesthesia and to investigate the potential role of intravenous lidocaine on colon cancer cell functions. We tested the effects of serum from colorectal cancer patients undergoing TIVA vs. sevoflurane anesthesia with or without lidocaine on HCT 116 cell lines; on proliferation, apoptosis, migration, and cell cycles; and on cancer-related gene expressions. Methods: 60 patients who were scheduled for colorectal cancer surgery were randomized into four different groups (two groups with TIVA and two groups with sevoflurane anesthesia with or without intravenous lidocaine). Blood samples were collected at the start and at the end of surgery. HCT 116 cells were exposed to the patients’ serum. Results: 15 patients were included in each of the study groups. We did not find any significant difference on cell viability or apoptosis between the study groups. However, there was an increased apoptosis in propofol groups, but this result was not statistically significant. A significant increase in the expression profile of the TP53 gene in the propofol group was registered (p = 0.029), while in the other study groups, no significant differences were reported. BCL2 and CASP3 expressions increased in the sevoflurane–lidocaine group without statistical significance. Conclusions: In our study, serum from patients receiving different anesthetic techniques did not significantly influence the apoptosis, migration, and cell cycle of HCT-116 colorectal carcinoma cells. Viability was also not significantly influenced by the anesthetic technique, except the sevoflurane–lidocaine group where it was increased. The gene expression of TP53 was significantly increased in the propofol group, which is consistent with the results of similar in vitro studies and may be one of the mechanisms by which anesthetic agents may influence the biology of cancer cells. Further studies that investigate the effects of propofol and lidocaine in different plasma concentrations on different colon cancer cell lines and assess the impacts of these findings on the clinical outcome are much needed. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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13 pages, 2059 KiB

Open AccessArticle

Gastric Cancer Cell-Derived Exosomal GRP78 Enhances Angiogenesis upon Stimulation of Vascular Endothelial Cells

by Kanako Iha, Akane Sato, Hsin-Yi Tsai, Hikaru Sonoda, Satoshi Watabe, Teruki Yoshimura, Ming-Wei Lin and Etsuro Ito

Curr. Issues Mol. Biol. 2022, 44(12), 6145-6157; https://doi.org/10.3390/cimb44120419 - 06 Dec 2022

Cited by 7 | Viewed by 1720

Abstract

Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in [...] Read more.

Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in the exosomes. Recently, exosomal GRP78 concentrations were successfully measured using an ultrasensitive ELISA. In the present study, GRP78 concentrations in exosomes collected from gastric cancer AGS cells with overexpression of GRP78 (OE), knockdown of GRP78 (KD), or mock GRP78 (mock) were quantified. These three types of exosomes were then incubated with vascular endothelial cells to examine their effects on endothelial cell angiogenesis. Based on the results of a tube formation assay, GRP78-OE exosomes accelerated angiogenesis compared with GRP78-KD or GRP78-mock exosomes. To investigate the mechanisms underlying this effect, we examined the Ser473 phosphorylation state ratio of AKT, which is involved in the angiogenesis process, and found that AKT phosphorylation was increased by GRP78-OE exosome application to the endothelial cells. An MTT assay showed that GRP78-OE exosome treatment increased the proliferation rate of endothelial cells, and a wound healing assay showed that this treatment increased the migration capacity of the endothelial cells. These findings demonstrated that GRP78-containing exosomes promote the tumor microenvironment and induce angiogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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9 pages, 1085 KiB

Open AccessArticle

API-2-Induced Cell Migration Is Overcome by Small Molecular Approaches Inhibiting β-Catenin

by Yonghyo Kim, Myoung-Hee Kang and Yong-Hee Cho

Curr. Issues Mol. Biol. 2022, 44(12), 6006-6014; https://doi.org/10.3390/cimb44120409 - 29 Nov 2022

Cited by 1 | Viewed by 1247

Abstract

Frequent mutation of APC (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/β-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear β-catenin-induced EMT and bypassing apoptosis. In this [...] Read more.

Frequent mutation of APC (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/β-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear β-catenin-induced EMT and bypassing apoptosis. In this study, we discover that the combinatorial treatment of an AKT inhibitor and KY1022, a β-catenin destabilizer, effectively overcomes the current limitations of API-2, an AKT inhibitor, by reducing nuclear β-catenin. Taken together, we demonstrate that the simultaneous suppression of Wnt/β-catenin with the AKT signaling pathways is an ideal strategy for suppressing the AKT-inhibitor-mediated metastasis and for maximizing the therapeutic effects of AKT inhibitors. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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12 pages, 1587 KiB

Open AccessArticle

Somatic Mutations Alter Interleukin Signaling Pathways in Grade II Invasive Breast Cancer Patients: An Egyptian Experience

by Auhood Nassar, Abdel Rahman N. Zekri, Mostafa H. Elberry, Ahmed M. Lymona, Mai M. Lotfy, Mohamed Abouelhoda and Amira Salah El-Din Youssef

Curr. Issues Mol. Biol. 2022, 44(12), 5890-5901; https://doi.org/10.3390/cimb44120401 - 26 Nov 2022

Cited by 1 | Viewed by 1520

Abstract

This study aimed to investigate the impact of somatic mutations on various interleukin signaling pathways associated with grade II invasive breast cancer (BC) in Egyptian patients to broaden our understanding of their role in promoting carcinogenesis. Fifty-five grade II invasive BC patients were [...] Read more.

This study aimed to investigate the impact of somatic mutations on various interleukin signaling pathways associated with grade II invasive breast cancer (BC) in Egyptian patients to broaden our understanding of their role in promoting carcinogenesis. Fifty-five grade II invasive BC patients were included in this study. Data for somatic mutations in 45 BC patients were already available from a previous study. Data for somatic mutations of 10 new BC patients were included in the current study. Somatic mutations were identified using targeted next-generation sequencing (NGS) to study their involvement in interleukin signaling pathways. For pathway analysis, we used ingenuity variant analysis (IVA) to identify the most significantly altered pathways. We identified somatic mutations in components of the interleukin-2, interleukin-6, and inter-leukin-7 signaling pathways, including mutations in JAK1, JAK2, JAK3, SOCS1, IL7R, MCL1, BCL2, MTOR, and IL6ST genes. Interestingly, six mutations which were likely to be novel deleterious were identified: two in the SCH1 gene, two in the IL2 gene, and one in each of the IL7R and JUN genes. According to IVA analysis, interleukin 2, interleukin 6, and interleukin 7 signaling pathways were the most altered in 34.5%, 29%, and 23.6% of our BC group, respectively. Our multigene panel sequencing analysis reveals that our BC patients have altered interleukin signaling pathways. So, these results highlight the prominent role of interleukins in the carcinogenesis process and suggest its potential role as promising candidates for personalized therapy in Egyptian patients. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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14 pages, 5544 KiB

Open AccessArticle

Immune Pathway and Gene Database (IMPAGT) Revealed the Immune Dysregulation Dynamics and Overactivation of the PI3K/Akt Pathway in Tumor Buddings of Cervical Cancer

by Yeseul Choi, Nora Jee-Young Park, Tan Minh Le, Eunmi Lee, Donghyeon Lee, Hong Duc Thi Nguyen, Junghwan Cho, Ji-Young Park, Hyung Soo Han and Gun Oh Chong

Curr. Issues Mol. Biol. 2022, 44(11), 5139-5152; https://doi.org/10.3390/cimb44110350 - 23 Oct 2022

Cited by 4 | Viewed by 1730

Abstract

Tumor budding (TB) is a small cluster of malignant cells at the invasive front of a tumor. Despite being an adverse prognosis marker, little research has been conducted on the tumor immune microenvironment of tumor buddings, especially in cervical cancer. Therefore, RNA sequencing [...] Read more.

Tumor budding (TB) is a small cluster of malignant cells at the invasive front of a tumor. Despite being an adverse prognosis marker, little research has been conducted on the tumor immune microenvironment of tumor buddings, especially in cervical cancer. Therefore, RNA sequencing was performed using 21 formalin-fixed, paraffin-embedded slides of cervical tissues, and differentially expressed genes (DEGs) were analyzed. Immune Pathway and Gene Database (IMPAGT) was generated for immune profiling. “Pathway in Cancer” was identified as the most enriched pathway for both up- and downregulated DEGs. Kyoto Encyclopedia of Genes and Genomes Mapper and Gene Ontology further revealed the activation of the PI3K/Akt signaling pathway. An IMPAGT analysis revealed immune dysregulation even at the tumor budding stage, especially in the PI3K/Akt/mTOR axis, with a high efficiency and integrity. These findings emphasized the clinical significance of tumor buddings and the necessity of blocking the overactivation of the PI3K/Akt/mTOR pathway to improve targeted therapy in cervical cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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13 pages, 1377 KiB

Open AccessArticle

Chemokine Homeostasis in Healthy Volunteers and during Pancreatic and Colorectal Tumor Growth in Murine Models

by Elena V. Svirshchevskaya, Mariya V. Konovalova, Eugene V. Snezhkov, Rimma A. Poltavtseva and Sergey B. Akopov

Curr. Issues Mol. Biol. 2022, 44(10), 4987-4999; https://doi.org/10.3390/cimb44100339 - 18 Oct 2022

Cited by 1 | Viewed by 1550

Abstract

Chemokines are involved in the humoral regulation of body homeostasis. Changes in the blood level of chemokines were found in cancer, atherosclerosis, diabetes, and other systemic diseases. It is essential to distinguish the effects of co-morbid pathologies and cancer on the level of [...] Read more.

Chemokines are involved in the humoral regulation of body homeostasis. Changes in the blood level of chemokines were found in cancer, atherosclerosis, diabetes, and other systemic diseases. It is essential to distinguish the effects of co-morbid pathologies and cancer on the level of chemokines in the blood. We aimed to analyze, by multiplex cytometry, the levels of chemokines in the blood of healthy young volunteers as well as of intact mice and mice with CT26 colon and Pan02 pancreatic tumors. Two types of chemokines were identified both in human and murine plasmas: homeostatic ones, which were found in high concentrations (>100 pg/mL), and inducible ones, which can be undetectable or determined at very low levels (0–100 pg/mL). There was a high variability in the chemokine levels, both in healthy humans and mice. To analyze chemokine levels during tumor growth, C57BL/6 and BALB/c were inoculated with Pan02 or CT26 tumor cells, accordingly. The tumors significantly differed in the growth and the mortality of mice. However, the blood chemokine levels did not change in tumor-bearing mice until the very late stages. Taken collectively, blood chemokine level is highly variable and reflects in situ homeostasis. Care should be taken when considering chemokines as prognostic parameters or therapeutic targets in cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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9 pages, 2296 KiB

Open AccessArticle

Expression of AKT1 Related with Clinicopathological Parameters in Clear Cell Renal Cell Carcinoma

by Taesoo Choi, Koo Han Yoo and Man S. Kim

Curr. Issues Mol. Biol. 2022, 44(10), 4921-4929; https://doi.org/10.3390/cimb44100334 - 15 Oct 2022

Cited by 3 | Viewed by 1328

Abstract

Pathways such as VEGF, EGF and mTOR are known to be one of the major mechanisms of tumorigenesis including kidney cancer. To identify potential signaling pathway proteins, we performed differential/correlation analyses of mTOR-associated genes from three public datasets. AKT1 protein, one of the [...] Read more.

Pathways such as VEGF, EGF and mTOR are known to be one of the major mechanisms of tumorigenesis including kidney cancer. To identify potential signaling pathway proteins, we performed differential/correlation analyses of mTOR-associated genes from three public datasets. AKT1 protein, one of the PI3K/AKT/mTOR pathways, turned out to be the potential by showing a consistent discrepancy between ccRCC-associated conditions as well as strong correlation with other mTOR-associated genes across the datasets. Then, we analyzed how AKT1 alteration affects clear cell renal cell carcinoma. The pathology of 58 kidney cancer patients was constructed to analyze the relationship between the expression level of AKT1 through immunohistochemical staining and their clinicopathological data. Gender, age and TNM stage did not show significant results. AKT1 is a known oncogene. However, in this study, high expression of AKT1 showed a slight correlation with lower WHO/ISUP grade, longer recurrence-free and progression-free survival rates. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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19 pages, 4957 KiB

Open AccessArticle

Induction of Breast Cancer Cell Apoptosis by TRAIL and Smac Mimetics: Involvement of RIP1 and cFLIP

by Christian Holmgren, Ellen Sunström Thörnberg, Victoria Granqvist and Christer Larsson

Curr. Issues Mol. Biol. 2022, 44(10), 4803-4821; https://doi.org/10.3390/cimb44100327 - 11 Oct 2022

Cited by 1 | Viewed by 1606

Abstract

Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are [...] Read more.

Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are however not fully understood. In this study, we aimed to shed light on these mechanisms in breast cancer cells. Three breast cancer cell lines, MDA-MB-468, CAMA-1 and MCF-7, were used to evaluate the effects of Smac mimetic LCL-161 and TRAIL using cell death assays and Western blot. The combination treatment induces apoptosis and caspase-8 cleavage in MDA-MB-468 and CAMA-1 but not in MCF-7 cells and downregulation of caspase-8 blocked apoptosis. Downregulation, but not kinase inhibition, of receptor-interacting protein 1 (RIP1) suppressed apoptosis in CAMA-1. Apoptosis is preceded by association of RIP1 with caspase-8. Downregulating cellular FLICE-like inhibitory protein (c-FLIP) resulted in increased caspase cleavage and some induction of apoptosis by TRAIL and LCL-161 in MCF-7. In CAMA-1, c-FLIP depletion potentiated TRAIL-induced caspase cleavage and LCL-161 did not increase it further. Our results lend further support to a model where LCL-161 enables the formation of a complex including RIP1 and caspase-8 and circumvents c-FLIP-mediated inhibition of caspase activation. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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16 pages, 2016 KiB

Open AccessArticle

Pro-Inflammatory and Anti-Inflammatory Salivary Cytokines in Breast Cancer: Relationship with Clinicopathological Characteristics of the Tumor

by Lyudmila V. Bel’skaya, Alexandra I. Loginova and Elena A. Sarf

Curr. Issues Mol. Biol. 2022, 44(10), 4676-4691; https://doi.org/10.3390/cimb44100319 - 06 Oct 2022

Cited by 5 | Viewed by 1708

Abstract

The aim of the work was to compare the salivary cytokine profile of breast cancer patients with the clinicopathological characteristics of the tumor. The study included 113 patients with breast cancer (main group, mean age 54.1 years) and 111 patients with breast fibroadenomas [...] Read more.

The aim of the work was to compare the salivary cytokine profile of breast cancer patients with the clinicopathological characteristics of the tumor. The study included 113 patients with breast cancer (main group, mean age 54.1 years) and 111 patients with breast fibroadenomas (control group, mean age 56.7 years). Before treatment, saliva samples were collected from all patients and the content of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, MCP-1, and TNF-α) was determined. The content of cytokines in saliva correlates well with the clinicopathological characteristics of breast cancer. The level of all salivary cytokines increases at advanced stages of breast cancer and at a low degree of tumor differentiation. The exception is MCP-1, for which there is an extremely high content for well-differentiated breast cancer. A statistically significant increase in the content of MCP-1, IL-1β, IL-2, IL-4, and IL-10 was found in triple-negative breast cancer. For the first time, the correlation of salivary levels of TNF-α, IL-1β, and IL-6 with HER2 status, MCP-1, IL-1β, IL-2, and IL-4 with the hormonal status of the tumor was shown. The relationship between the level of IL-2, IL-10, and IL-18 in saliva with the level of Ki-67 expression has been established. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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11 pages, 816 KiB

Open AccessArticle

ADAM10 and ADAM17 as Biomarkers Linked to Inflammation, Metabolic Disorders and Colorectal Cancer

by Magdalena Sikora-Skrabaka, Katarzyna Weronika Walkiewicz, Ewa Nowakowska-Zajdel, Dariusz Waniczek and Joanna Katarzyna Strzelczyk

Curr. Issues Mol. Biol. 2022, 44(10), 4517-4527; https://doi.org/10.3390/cimb44100309 - 29 Sep 2022

Cited by 2 | Viewed by 1682

Abstract

ADAM10 and ADAM17 have a role in inflammation and diseases associated with inflammation, such as diabetes, cardiovascular diseases (CVD) or cancer, e.g., colorectal cancer (CRC). The aim of this study was to evaluate whether ADAM10 and ADAM17 could be biomarkers of CRC. To [...] Read more.

ADAM10 and ADAM17 have a role in inflammation and diseases associated with inflammation, such as diabetes, cardiovascular diseases (CVD) or cancer, e.g., colorectal cancer (CRC). The aim of this study was to evaluate whether ADAM10 and ADAM17 could be biomarkers of CRC. To achieve this goal, CRC tumors and a surgical margin from 72 patients with CRC were collected. The concentration of ADAM proteins was measured by the ELISA method. Results were analyzed statistically and compared with selected clinical parameters. We found that ADAM17 protein concentration in the tumor samples was higher in patients with diabetes mellitus type 2 (DMT2) (0.28 vs. 0.2 ng/µg protein; p = 0.01) and in the surgical margin was higher both in patients with coexisting DMT2 (0.22 vs. 0.16 ng/µg protein; p < 0.05) and CVD (0.21 vs. 0.13 ng/µg protein; p < 0.01). The concentration of ADAM10 was higher in the surgical margin than in the tumor (249.34 vs. 228.82 pg/µg protein), and the concentration of ADAM17 was higher in the tumor than in the margin (0.23 vs. 0.18 ng/µg protein), but results were not statistically significant. In conclusion, the results of our study indicate that ADAM10 and ADAM17 may be potential biomarkers in cancer linked with DMT2 and CVD as diseases associated with inflammation. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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21 pages, 3776 KiB

Open AccessArticle

Exploring the Novel Computational Drug Target and Associated Key Pathways of Oral Cancer

by Fatema Akhter, Fawzia Haif Al Kahtani, Zainah Mohammed Sambawa, Deema Abdulrahman Alhassan, Reema Abdulaziz AlSaif, Tahsinul Haque, Mohammad Khursheed Alam, Md. Tanvir Hasan, Md. Rakibul Islam, Kawsar Ahmed and Rehana Basri

Curr. Issues Mol. Biol. 2022, 44(8), 3552-3572; https://doi.org/10.3390/cimb44080244 - 09 Aug 2022

Viewed by 2363

Abstract

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft [...] Read more.

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. The publicly available repository the Gene Expression Omnibus (GEO) was to the source for the collection of OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected for analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to calculate the upregulated and downregulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein–protein interaction (PPI) networks were built to identify the most active genes, and a clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study OC-associated DEGs in-depth. Finally, top gene performers from PPI networks were used to apply drug signature analysis. After applying filtration and cut-off criteria, 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the cell cycle and influenza A. The PPI network holds 88 nodes and 492 edges, and CDC6 had the highest number of connections. Four clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of OC pathophysiology and the development of new therapies for OC. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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17 pages, 6376 KiB

Open AccessArticle

The Aminoacyl-tRNA Synthetase and tRNA Expression Levels Are Deregulated in Cancer and Correlate Independently with Patient Survival

by Anmolpreet Kaur Sangha and Theodoros Kantidakis

Curr. Issues Mol. Biol. 2022, 44(7), 3001-3017; https://doi.org/10.3390/cimb44070207 - 02 Jul 2022

Cited by 6 | Viewed by 3572

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that load amino acids to their cognate tRNA molecules. The expression of certain ARSs and tRNAs has been shown to be deregulated in cancer, presumably to accommodate elevated protein synthesis requirements. In this work, the expression of [...] Read more.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that load amino acids to their cognate tRNA molecules. The expression of certain ARSs and tRNAs has been shown to be deregulated in cancer, presumably to accommodate elevated protein synthesis requirements. In this work, the expression of cytoplasmic ARSs and tRNAs in ten TCGA cancers has been systematically examined. ARSs were found to be mostly upregulated in tumours and their upregulation often correlated with worse patient survival. tRNAs were found to be either upregulated or downregulated in tumours and their expression sometimes correlated to worse survival outcomes. However, although the expression of most ARSs and tRNAs was deregulated in tumours when compared to healthy adjacent tissues, only in a few cases, and independently, did it correlate to patient survival. These data point to the general uncoupling of concomitant ARS and tRNA expression deregulation and patient survival, highlighting the different ARS and tRNA requirements in cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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19 pages, 2510 KiB

Open AccessArticle

Using AI-Based Evolutionary Algorithms to Elucidate Adult Brain Tumor (Glioma) Etiology Associated with IDH1 for Therapeutic Target Identification

by Caitríona E. McInerney, Joanna A. Lynn, Alan R. Gilmore, Tom Flannery and Kevin M. Prise

Curr. Issues Mol. Biol. 2022, 44(7), 2982-3000; https://doi.org/10.3390/cimb44070206 - 02 Jul 2022

Cited by 1 | Viewed by 2803

Abstract

Adult brain tumors (glioma) represent a cancer of unmet need where standard-of-care is non-curative; thus, new therapies are urgently needed. It is unclear whether isocitrate dehydrogenases (IDH1/2) when not mutated have any role in gliomagenesis or tumor growth. Nevertheless, IDH1 is overexpressed in [...] Read more.

Adult brain tumors (glioma) represent a cancer of unmet need where standard-of-care is non-curative; thus, new therapies are urgently needed. It is unclear whether isocitrate dehydrogenases (IDH1/2) when not mutated have any role in gliomagenesis or tumor growth. Nevertheless, IDH1 is overexpressed in glioblastoma (GBM), which could impact upon cellular metabolism and epigenetic reprogramming. This study characterizes IDH1 expression and associated genes and pathways. A novel biomarker discovery pipeline using artificial intelligence (evolutionary algorithms) was employed to analyze IDH-wildtype adult gliomas from the TCGA LGG-GBM cohort. Ninety genes whose expression correlated with IDH1 expression were identified from: (1) All gliomas, (2) primary GBM, and (3) recurrent GBM tumors. Genes were overrepresented in ubiquitin-mediated proteolysis, focal adhesion, mTOR signaling, and pyruvate metabolism pathways. Other non-enriched pathways included O-glycan biosynthesis, notch signaling, and signaling regulating stem cell pluripotency (PCGF3). Potential prognostic (TSPYL2, JAKMIP1, CIT, TMTC1) and two diagnostic (MINK1, PLEKHM3) biomarkers were downregulated in GBM. Their gene expression and methylation were negatively and positively correlated with IDH1 expression, respectively. Two diagnostic biomarkers (BZW1, RCF2) showed the opposite trend. Prognostic genes were not impacted by high frequencies of molecular alterations and only one (TMTC1) could be validated in another cohort. Genes with mechanistic links to IDH1 were involved in brain neuronal development, cell proliferation, cytokinesis, and O-mannosylation as well as tumor suppression and anaplerosis. Results highlight metabolic vulnerabilities and therapeutic targets for use in future clinical trials. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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15 pages, 1806 KiB

Open AccessArticle

Inflammatory Breast Cancer: The Cytokinome of Post-Mastectomy Wound Fluid Augments Proliferation, Invasion, and Stem Cell Markers

by Alshaimaa Tarek, Shrouk Khalaf El-Sayed, Wendy A. Woodward, Mohamed El-Shinawi, Jon Mark Hirshon and Mona Mostafa Mohamed

Curr. Issues Mol. Biol. 2022, 44(6), 2730-2744; https://doi.org/10.3390/cimb44060187 - 17 Jun 2022

Cited by 1 | Viewed by 2058

Abstract

Inflammatory breast cancer (IBC) is an aggressive phenotype with a high recurrence and low survival rate. Approximately 90% of local breast cancer recurrences occur adjacent to the same quadrant as the initial cancer, implying that tumor recurrence may be caused by residual cancer [...] Read more.

Inflammatory breast cancer (IBC) is an aggressive phenotype with a high recurrence and low survival rate. Approximately 90% of local breast cancer recurrences occur adjacent to the same quadrant as the initial cancer, implying that tumor recurrence may be caused by residual cancer cells and/or quiescent cancer stem cells (CSCs) in the tumor. We hypothesized that wound fluid (WF) collected after modified radical mastectomy (MRM) may activate cancer cells and CSCs, promoting epithelial mesenchymal transition (EMT) and invasion. Therefore, we characterized the cytokinome of WF drained from post-MRM cavities of non-IBC and IBC patients. The WF of IBC patients showed a significantly higher expression of various cytokines than in non-IBC patients. In vitro cell culture models of non-IBC and IBC cell lines were grown in media conditioned with and/without WF for 48 h. Afterwards, we assessed cell viability, the expression of CSCs and EMT-specific genes, and tumor invasion. Genes associated with CSCs properties and EMT markers were regulated in cells seeded in media conditioned by WF. IBC-WF exhibited a greater potential for inducing IBC cell invasion than non-IBC cells. The present study demonstrates the role of the post-surgical tumor cavity in IBC recurrence and metastasis. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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23 pages, 4133 KiB

Open AccessReview

Moringa oleifera: A Review on the Antiproliferative Potential in Breast Cancer Cells

by Malebogo M. Moremane, Beynon Abrahams and Charlette Tiloke

Curr. Issues Mol. Biol. 2023, 45(8), 6880-6902; https://doi.org/10.3390/cimb45080434 - 18 Aug 2023

Cited by 3 | Viewed by 1706

Abstract

The global burden of female breast cancer and associated deaths has become a major concern. Many chemotherapeutic agents, such as doxorubicin, have been shown to have adverse side effects. The development of multi-drug resistance is a common occurrence, contributing to chemotherapeutic failure. The [...] Read more.

The global burden of female breast cancer and associated deaths has become a major concern. Many chemotherapeutic agents, such as doxorubicin, have been shown to have adverse side effects. The development of multi-drug resistance is a common occurrence, contributing to chemotherapeutic failure. The resistance of breast cancer cells to drug treatment leads to a decline in the treatment efficacy and an increase in cancer recurrence. Therefore, action is required to produce alternative drug therapies, such as herbal drugs. Herbal drugs have been proven to be beneficial in treating illnesses, including cancer. This review aims to highlight the antiproliferative potential of Moringa oleifera (MO), a medicinal tree native to India and indigenous to Africa, in breast cancer cells. Although MO is not yet considered a commercial chemopreventive drug, previous studies have indicated that it could become a chemotherapeutic agent. The possible antiproliferative potential of MO aqueous leaf extract has been previously proven through its antioxidant potential as well as its ability to induce apoptosis. This review will provide an increased understanding of the effect that MO aqueous leaf extract could potentially have against breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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23 pages, 356 KiB

Open AccessReview

Pathology and Molecular Biology of Melanoma

by Tanase Timis, Jon Thor Bergthorsson, Victor Greiff, Mihai Cenariu and Diana Cenariu

Curr. Issues Mol. Biol. 2023, 45(7), 5575-5597; https://doi.org/10.3390/cimb45070352 - 30 Jun 2023

Cited by 3 | Viewed by 1916

Abstract

Almost every death in young patients with an advanced skin tumor is caused by melanoma. Today, with the help of modern treatments, these patients survive longer or can even achieve a cure. Advanced stage melanoma is frequently related with poor prognosis and physicians [...] Read more.

Almost every death in young patients with an advanced skin tumor is caused by melanoma. Today, with the help of modern treatments, these patients survive longer or can even achieve a cure. Advanced stage melanoma is frequently related with poor prognosis and physicians still find this disease difficult to manage due to the absence of a lasting response to initial treatment regimens and the lack of randomized clinical trials in post immunotherapy/targeted molecular therapy settings. New therapeutic targets are emerging from preclinical data on the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of malignant transformation. In the current paper, we present the diagnostic challenges, molecular biology and genetics of malignant melanoma, as well as the current therapeutic options for patients with this diagnosis. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

32 pages, 1679 KiB

Open AccessReview

Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia

by Jose M. Prieto and Mohd Mukrish Mohd Hanafi

Curr. Issues Mol. Biol. 2023, 45(2), 1536-1567; https://doi.org/10.3390/cimb45020099 - 09 Feb 2023

Cited by 4 | Viewed by 2918

Abstract

Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as [...] Read more.

Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum (syn. Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri. Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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11 pages, 1361 KiB

Open AccessOpinion

Review on Advanced Cancer Modeling for a Cancer Study

by Yong-Hee Cho

Curr. Issues Mol. Biol. 2022, 44(11), 5352-5362; https://doi.org/10.3390/cimb44110362 - 31 Oct 2022

Viewed by 1426

Abstract

Intensive efforts to develop anti-cancer agents have been made for over 60 years. However, cancer is still considered a lethal disease. To study the best anti-cancer agents for improving the survival rates of cancer patients, many researchers have focused on establishing advanced experimental [...] Read more.

Intensive efforts to develop anti-cancer agents have been made for over 60 years. However, cancer is still considered a lethal disease. To study the best anti-cancer agents for improving the survival rates of cancer patients, many researchers have focused on establishing advanced experimental applications reflecting on the biomimetics of cancer patients involving the heterogeneity of cancer cells. The heterogeneity of cancer cells, which are derived from various clones and affected by different environments, presents different genetic backgrounds and molecular characteristics attributed to the differential responses to cancer therapies, and these are responsible for the resistance to cancer therapies, as well as for recurrence following cancer treatments. Therefore, the development of advanced applications for the cancer patient is expected to help the development of more effective anti-cancer agents. The present review evaluates recently developed cancer models encompassing the heterogeneity of cancer cells, which present similar morphological architecture, genetic backgrounds, and molecular characteristics to corresponding patient tumor tissues. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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9 pages, 537 KiB

Open AccessBrief Report

Molecular Profiling of Tumor Tissue in Mexican Patients with Colorectal Cancer

by Beatriz Armida Flores-López, María de la Luz Ayala-Madrigal, José Miguel Moreno-Ortiz, Jorge Peregrina-Sandoval, Miguel Ángel Trujillo-Rojas, José Luis Venegas-Rodríguez, Rosario Hernández-Ramírez, Martha Alejandra Fernández-Galindo and Melva Gutiérrez-Angulo

Curr. Issues Mol. Biol. 2022, 44(8), 3770-3778; https://doi.org/10.3390/cimb44080258 - 20 Aug 2022

Viewed by 1738

Abstract

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with [...] Read more.

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with colorectal cancer, using massive parallel sequencing. A total of 4813 genes were analyzed in tumoral DNA from colorectal cancer patients, using the TruSight One Sequencing panel. From these, 192 variants with clinical associations were found distributed in 168 different genes, of which 46 variants had not been previous reported in the literature or databases, although genes harboring those variants had already been described in colorectal cancer. Enrichment analysis of the affected genes was performed using Reactome software; pathway over-representation showed significance for disease, signal transduction, and immune system subsets in all patients, while exclusive subsets such as DNA repair, autophagy, and RNA metabolism were also found. Those characteristics, whether individual or shared, could give tumors specific capabilities for survival, aggressiveness, or response to treatment. Our results can be useful for future investigations targeting specific characteristics of tumors in colorectal cancer patients. The identification of exclusive or common pathways in colorectal cancer patients could be important for better diagnosis and personalized cancer treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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