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14 pages, 2693 KiB

Open AccessArticle

The EGFR Signaling Modulates in Mesenchymal Stem Cells the Expression of miRNAs Involved in the Interaction with Breast Cancer Cells

by Marianna Gallo, Marianeve Carotenuto, Daniela Frezzetti, Rosa Camerlingo, Cristin Roma, Francesca Bergantino, Nicola Normanno and Antonella De Luca

Cancers 2022, 14(7), 1851; https://doi.org/10.3390/cancers14071851 - 06 Apr 2022

Cited by 4 | Viewed by 1708

Abstract

We previously demonstrated that the epidermal growth factor receptor (EGFR) modulates in mesenchymal stem cells (MSCs) the expression of a number of genes coding for secreted proteins that promote breast cancer progression. However, the role of the EGFR in modulating in MSCs the [...] Read more.

We previously demonstrated that the epidermal growth factor receptor (EGFR) modulates in mesenchymal stem cells (MSCs) the expression of a number of genes coding for secreted proteins that promote breast cancer progression. However, the role of the EGFR in modulating in MSCs the expression of miRNAs potentially involved in the progression of breast cancer remains largely unexplored. Following small RNA-sequencing, we identified 36 miRNAs differentially expressed between MSCs untreated or treated with the EGFR ligand transforming growth factor α (TGFα), with a fold change (FC) < 0.56 or FC ≥ 1.90 (CI, 95%). KEGG analysis revealed a significant enrichment in signaling pathways involved in cancer development and progression. EGFR activation in MSCs downregulated the expression of different miRNAs, including miR-23c. EGFR signaling also reduced the secretion of miR-23c in conditioned medium from MSCs. Functional assays demonstrated that miR-23c acts as tumor suppressor in basal/claudin-low MDA-MB-231 and MDA-MB-468 cells, through the repression of IL-6R. MiR-23c downregulation promoted cell proliferation, migration and invasion of these breast cancer cell lines. Collectively, our data suggested that the EGFR signaling regulates in MSCs the expression of miRNAs that might be involved in breast cancer progression, providing novel information on the mechanisms that regulate the MSC-tumor cell cross-talk. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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16 pages, 4544 KiB

Open AccessArticle

miR-214-3p Is Commonly Downregulated by EWS-FLI1 and by CD99 and Its Restoration Limits Ewing Sarcoma Aggressiveness

by Alessandra De Feo, Laura Pazzaglia, Lisa Ciuffarin, Fabio Mangiagli, Michela Pasello, Elisa Simonetti, Evelin Pellegrini, Cristina Ferrari, Giuseppe Bianchi, Benedetta Spazzoli and Katia Scotlandi

Cancers 2022, 14(7), 1762; https://doi.org/10.3390/cancers14071762 - 30 Mar 2022

Cited by 6 | Viewed by 2006

Abstract

Ewing’s sarcoma (EWS), an aggressive pediatric bone and soft-tissue sarcoma, has a very stable genome with very few genetic alterations. Unlike in most cancers, the progression of EWS appears to depend on epigenetic alterations. EWS–FLI1 and CD99, the two hallmarks of EWS, are [...] Read more.

Ewing’s sarcoma (EWS), an aggressive pediatric bone and soft-tissue sarcoma, has a very stable genome with very few genetic alterations. Unlike in most cancers, the progression of EWS appears to depend on epigenetic alterations. EWS–FLI1 and CD99, the two hallmarks of EWS, are reported to severely impact the malignancy of EWS cells, at least partly by regulating the expression of several types of non-coding RNAs. Here, we identify miR-214-3p as a common mediator of either EWS-FLI1 or CD99 by in silico analysis. MiR-214-3p expression was lower in EWS cells and in clinical samples than in bone marrow mesenchymal stem cells, and this miRNA was barely expressed in metastatic lesions. Silencing of EWS-FLI1 or CD99 restored the expression of miR-214-3p, leading to a reduced cell growth and migration. Mechanistically, miR-214-3p restoration inhibits the expression of the high-mobility group AT-hook 1 (HMGA1) protein, a validated target of miR-214-3p and a major regulator of the transcriptional machinery. The decrease in HMGA1 expression reduced the growth and the migration of EWS cells. Taken together, our results support that the miR-214-3p is constitutively repressed by both EWS-FLI1 and CD99 because it acts as an oncosuppressor limiting the dissemination of EWS cells. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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21 pages, 9867 KiB

Open AccessArticle

Identification of Let-7 miRNA Activity as a Prognostic Biomarker of SHH Medulloblastoma

by Maximillian S. Westphal, Eunjee Lee, Eric E. Schadt, Giselle S. Sholler and Jun Zhu

Cancers 2022, 14(1), 139; https://doi.org/10.3390/cancers14010139 - 28 Dec 2021

Cited by 3 | Viewed by 1725

Abstract

Medulloblastoma (MB) is the most common pediatric embryonal brain tumor. The current consensus classifies MB into four molecular subgroups: sonic hedgehog-activated (SHH), wingless-activated (WNT), Group 3, and Group 4. MYCN and let-7 play a critical role in MB. Thus, we inferred the activity [...] Read more.

Medulloblastoma (MB) is the most common pediatric embryonal brain tumor. The current consensus classifies MB into four molecular subgroups: sonic hedgehog-activated (SHH), wingless-activated (WNT), Group 3, and Group 4. MYCN and let-7 play a critical role in MB. Thus, we inferred the activity of miRNAs in MB by using the ActMiR procedure. SHH-MB has higher MYCN expression than the other subgroups. We showed that high MYCN expression with high let-7 activity is significantly associated with worse overall survival, and this association was validated in an independent MB dataset. Altogether, our results suggest that let-7 activity and MYCN can further categorize heterogeneous SHH tumors into more and less-favorable prognostic subtypes, which provide critical information for personalizing treatment options for SHH-MB. Comparing the expression differences between the two SHH-MB prognostic subtypes with compound perturbation profiles, we identified FGFR inhibitors as one potential treatment option for SHH-MB patients with the less-favorable prognostic subtype. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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21 pages, 2495 KiB

Open AccessArticle

Increased Plasma Levels of lncRNAs LINC01268, GAS5 and MALAT1 Correlate with Negative Prognostic Factors in Myelofibrosis

by Sebastian Fantini, Sebastiano Rontauroli, Stefano Sartini, Margherita Mirabile, Elisa Bianchi, Filippo Badii, Monica Maccaferri, Paola Guglielmelli, Tiziana Ottone, Raffaele Palmieri, Elena Genovese, Chiara Carretta, Sandra Parenti, Selene Mallia, Lara Tavernari, Costanza Salvadori, Francesca Gesullo, Chiara Maccari, Michela Zizza, Alexis Grande, Silvia Salmoiraghi, Barbara Mora, Leonardo Potenza, Vittorio Rosti, Francesco Passamonti, Alessandro Rambaldi, Maria Teresa Voso, Cristina Mecucci, Enrico Tagliafico, Mario Luppi, Alessandro Maria Vannucchi and Rossella Manfredini Show full author list Hide full author list

Cancers 2021, 13(19), 4744; https://doi.org/10.3390/cancers13194744 - 22 Sep 2021

Cited by 10 | Viewed by 2766

Abstract

Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. [...] Read more.

Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients’ cohort, it could be used for further studies to design an updated classification model for MF patients. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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38 pages, 8290 KiB

Open AccessArticle

Identification and Roles of miR-29b-1-3p and miR29a-3p-Regulated and Non-Regulated lncRNAs in Endocrine-Sensitive and Resistant Breast Cancer Cells

by Penn Muluhngwi and Carolyn M. Klinge

Cancers 2021, 13(14), 3530; https://doi.org/10.3390/cancers13143530 - 14 Jul 2021

Cited by 14 | Viewed by 3218

Abstract

Despite improvements in the treatment of endocrine-resistant metastatic disease using combination therapies in patients with estrogen receptor α (ERα) primary tumors, the mechanisms underlying endocrine resistance remain to be elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNA) and long non-coding RNAs (lncRNA), are targets [...] Read more.

Despite improvements in the treatment of endocrine-resistant metastatic disease using combination therapies in patients with estrogen receptor α (ERα) primary tumors, the mechanisms underlying endocrine resistance remain to be elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNA) and long non-coding RNAs (lncRNA), are targets and regulators of cell signaling pathways and their exosomal transport may contribute to metastasis. Previous studies have shown that a low expression of miR-29a-3p and miR-29b-3p is associated with lower overall breast cancer survival before 150 mos. Transient, modest overexpression of miR-29b1-3p or miR-29a-3p inhibited MCF-7 tamoxifen-sensitive and LCC9 tamoxifen-resistant cell proliferation. Here, we identify miR-29b-1/a-regulated and non-regulated differentially expressed lncRNAs in MCF-7 and LCC9 cells using next-generation RNA seq. More lncRNAs were miR-29b-1/a-regulated in LCC9 cells than in MCF-7 cells, including DANCR, GAS5, DSCAM-AS1, SNHG5, and CRND. We examined the roles of miR-29-regulated and differentially expressed lncRNAs in endocrine-resistant breast cancer, including putative and proven targets and expression patterns in survival analysis using the KM Plotter and TCGA databases. This study provides new insights into lncRNAs in endocrine-resistant breast cancer. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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14 pages, 1726 KiB

Open AccessArticle

Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma

by David E. Cohn, Mateus C. Barros-Filho, Brenda C. Minatel, Michelle E. Pewarchuk, Erin A. Marshall, Emily A. Vucic, Adam P. Sage, Nikita Telkar, Greg L. Stewart, Igor Jurisica, Patricia P. Reis, Wendy P. Robinson and Wan L. Lam

Cancers 2021, 13(11), 2686; https://doi.org/10.3390/cancers13112686 - 29 May 2021

Viewed by 2681

Abstract

MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal [...] Read more.

MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts (n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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25 pages, 5308 KiB

Open AccessArticle

Novel Long Noncoding RNA miR205HG Functions as an Esophageal Tumor-Suppressive Hedgehog Inhibitor

by Jee Hoon Song, Alan H. Tieu, Yulan Cheng, Ke Ma, Venkata S. Akshintala, Cem Simsek, Vishnu Prasath, Eun Ji Shin, Saowanee Ngamruengphong, Mouen A. Khashab, John M. Abraham and Stephen J. Meltzer

Cancers 2021, 13(7), 1707; https://doi.org/10.3390/cancers13071707 - 03 Apr 2021

Cited by 15 | Viewed by 2406

Abstract

Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways. However, involvement of lncRNAs in the development of BE and EAC has not been well-studied. The aims of the [...] Read more.

Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways. However, involvement of lncRNAs in the development of BE and EAC has not been well-studied. The aims of the current study were: (1) to study involvement of the lncRNA, miR205HG, in the development of BE and EAC; (2) to clarify the role of miR205HG in in vitro and in vivo experiments; and (3) to investigate the mechanism of miR205HG involving the Hedgehog (Hh) signaling pathway. These experiments revealed that miR205HG was downregulated in EAC vs. normal esophageal epithelia (NE) as well as in EAC cell lines, and its forced overexpression inhibited EAC cell proliferation and cell cycle progression in vitro. Similarly, overexpression of miR205HG inhibited xenograft tumor growth in mice In vivo. Finally, we show that one mechanism of action of miR205HG involves the Hh signaling pathway: miR205HG and Hh expression levels were inversely correlated in both EAC (r = −0.73) and BE (r = −0.83) tissues, and in vitro studies revealed details of Hh signaling inhibition induced by miR205HG. In conclusion, these findings establish that lncRNA miR205HG functions as a tumor suppressor in the development of BE and EAC, at least in part through its effect on the Hh signaling pathway. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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25 pages, 3852 KiB

Open AccessArticle

Cross-Linking Ligation and Sequencing of Hybrids (qCLASH) Reveals an Unpredicted miRNA Targetome in Melanoma Cells

by Ines Kozar, Demetra Philippidou, Christiane Margue, Lauren A. Gay, Rolf Renne and Stephanie Kreis

Cancers 2021, 13(5), 1096; https://doi.org/10.3390/cancers13051096 - 04 Mar 2021

Cited by 12 | Viewed by 3086

Abstract

MicroRNAs are key post-transcriptional gene regulators often displaying aberrant expression patterns in cancer. As microRNAs are promising disease-associated biomarkers and modulators of responsiveness to anti-cancer therapies, a solid understanding of their targetome is crucial. Despite enormous research efforts, the success rates of available [...] Read more.

MicroRNAs are key post-transcriptional gene regulators often displaying aberrant expression patterns in cancer. As microRNAs are promising disease-associated biomarkers and modulators of responsiveness to anti-cancer therapies, a solid understanding of their targetome is crucial. Despite enormous research efforts, the success rates of available tools to reliably predict microRNAs (miRNA)-target interactions remains limited. To investigate the disease-associated miRNA targetome, we have applied modified cross-linking ligation and sequencing of hybrids (qCLASH) to BRAF-mutant melanoma cells. The resulting RNA-RNA hybrid molecules provide a comprehensive and unbiased snapshot of direct miRNA-target interactions. The regulatory effects on selected miRNA target genes in predicted vs. non-predicted binding regions was validated by miRNA mimic experiments. Most miRNA–target interactions deviate from the central dogma of miRNA targeting up to 60% interactions occur via non-canonical seed pairing with a strong contribution of the 3′ miRNA sequence, and over 50% display a clear bias towards the coding sequence of mRNAs. miRNAs targeting the coding sequence can directly reduce gene expression (miR-34a/CD68), while the majority of non-canonical miRNA interactions appear to have roles beyond target gene suppression (miR-100/AXL). Additionally, non-mRNA targets of miRNAs (lncRNAs) whose interactions mainly occur via non-canonical binding were identified in melanoma. This first application of CLASH sequencing to cancer cells identified over 8 K distinct miRNA–target interactions in melanoma cells. Our data highlight the importance non-canonical interactions, revealing further layers of complexity of post-transcriptional gene regulation in melanoma, thus expanding the pool of miRNA–target interactions, which have so far been omitted in the cancer field. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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15 pages, 3176 KiB

Open AccessCommunication

LncRNA-mRNA Co-Expression Analysis Identifies AL133346.1/CCN2 as Biomarkers in Pediatric B-Cell Acute Lymphoblastic Leukemia

by Marta Cuadros, Daniel J. García, Alvaro Andrades, Alberto M. Arenas, Isabel F. Coira, Carlos Baliñas-Gavira, Paola Peinado, María I. Rodríguez, Juan Carlos Álvarez-Pérez, Francisco Ruiz-Cabello, Mireia Camós, Antonio Jiménez-Velasco and Pedro P. Medina

Cancers 2020, 12(12), 3803; https://doi.org/10.3390/cancers12123803 - 17 Dec 2020

Cited by 8 | Viewed by 3316

Abstract

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing [...] Read more.

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with “high” expression levels of CCN2 had higher overall survival than those with “low” levels (p = 0.042), and this gene might be an independent prognostic biomarker in pediatric B-ALL. These findings provide one of the first detailed descriptions of lncRNA expression profiles in pediatric B-ALL and indicate that these potential biomarkers could help in the classification of leukemia subtypes and that CCN2 expression could predict the survival outcome of pediatric B-cell acute lymphoblastic leukemia patients. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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Review

Jump to: Research

26 pages, 2919 KiB

Open AccessReview

Noncoding RNAs in Thyroid-Follicular-Cell-Derived Carcinomas

by Marco De Martino, Francesco Esposito, Maria Capone, Pierlorenzo Pallante and Alfredo Fusco

Cancers 2022, 14(13), 3079; https://doi.org/10.3390/cancers14133079 - 23 Jun 2022

Cited by 6 | Viewed by 2198

Abstract

Among the thyroid neoplasias originating from follicular cells, we can include well-differentiated carcinomas, papillary (PTC) and follicular (FTC) thyroid carcinomas, and the undifferentiated anaplastic (ATC) carcinomas. Several mutations in oncogenes and tumor suppressor genes have already been observed in these malignancies; however, we [...] Read more.

Among the thyroid neoplasias originating from follicular cells, we can include well-differentiated carcinomas, papillary (PTC) and follicular (FTC) thyroid carcinomas, and the undifferentiated anaplastic (ATC) carcinomas. Several mutations in oncogenes and tumor suppressor genes have already been observed in these malignancies; however, we are still far from the comprehension of their full regulation-altered landscape. Even if only 2% of the human genome has the ability to code for proteins, most of the noncoding genome is transcribed, constituting the heterogeneous class of noncoding RNAs (ncRNAs), whose alterations are associated with the development of several human diseases, including cancer. Hence, many scientific efforts are currently focused on the elucidation of their biological role. In this review, we analyze the scientific literature regarding the involvement of microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and pseudogenes in FTC, PTC, and ATC. Recent findings emphasized the role of lncRNAs in all steps of cancer progression. In particular, lncRNAs may control progression steps by regulating the expression of genes and miRNAs involved in cell proliferation, apoptosis, epithelial–mesenchymal transition, and metastatization. In conclusion, the determination of the diagnosis, prognosis, and treatment of cancer based on the evaluation of the ncRNA network could allow the implementation of a more personalized approach to fighting thyroid tumors. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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40 pages, 1663 KiB

Open AccessReview

Overview on Molecular Biomarkers for Laryngeal Cancer: Looking for New Answers to an Old Problem

by Michela Falco, Chiara Tammaro, Takashi Takeuchi, Alessia Maria Cossu, Giuseppe Scafuro, Silvia Zappavigna, Annalisa Itro, Raffaele Addeo, Marianna Scrima, Angela Lombardi, Filippo Ricciardiello, Carlo Irace, Michele Caraglia and Gabriella Misso

Cancers 2022, 14(7), 1716; https://doi.org/10.3390/cancers14071716 - 28 Mar 2022

Cited by 12 | Viewed by 4262

Abstract

Laryngeal squamous cell cancer (LSCC) accounts for almost 25–30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving [...] Read more.

Laryngeal squamous cell cancer (LSCC) accounts for almost 25–30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising as they circulate in all the biological fluids allowing liquid biopsy determination, as well as due to their quick and characteristic modulation useful for non-invasive detection and monitoring of cancer. Other critical aspects are related to recent progress in circulating tumor cells and DNA detection, in metastatic status and chemo-refractoriness prediction, and in the functional interaction of LSCC with chronic inflammation and innate immunity. We review all these aspects taking into account the progress of the technologies in the field of next generation sequencing. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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11 pages, 10534 KiB

Open AccessEditor’s ChoiceReview

Diverse Roles and Targets of miRNA in the Pathogenesis of Testicular Germ Cell Tumour

by Mrinal K. Das, Øyvind P. Haugen and Trine B. Haugen

Cancers 2022, 14(5), 1190; https://doi.org/10.3390/cancers14051190 - 25 Feb 2022

Cited by 9 | Viewed by 2375

Abstract

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association [...] Read more.

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association studies have so far found 78 susceptibility loci for TGCT, and many of the loci are in non-coding regions indicating the involvement of non-coding RNAs in TGCT pathogenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, have emerged as important gene regulators at the post-transcriptional level. They are crucial in controlling many cellular processes, such as proliferation, differentiation, and apoptosis, and an aberrant miRNA expression may contribute to the pathogenesis of several cancers, including TGCT. In support of this notion, several studies reported differential expression of miRNAs in TGCTs. We previously demonstrated that miRNAs were the most common group of small non-coding RNAs in TGCTs, and several functional studies of miRNAs in TGCTs suggest that they may act as either oncogene or tumour suppressors. Moreover, individual miRNA targets and downstream pathways in the context of TGCT development have been explored. In this review, we will focus on the diverse roles and targets of miRNAs in TGCT pathogenesis. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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18 pages, 1009 KiB

Open AccessReview

Small Non-Coding RNAs in Leukemia

by Veronica Balatti and Carlo M. Croce

Cancers 2022, 14(3), 509; https://doi.org/10.3390/cancers14030509 - 20 Jan 2022

Cited by 7 | Viewed by 1811

Abstract

In 2020, more than 60,500 people were diagnosed with leukemia in the USA, and more than 23,000 died. The incidence of leukemia is still rising, and drug resistance development is a serious concern for patients’ wellbeing and survival. In the past two decades, [...] Read more.

In 2020, more than 60,500 people were diagnosed with leukemia in the USA, and more than 23,000 died. The incidence of leukemia is still rising, and drug resistance development is a serious concern for patients’ wellbeing and survival. In the past two decades, small non-coding RNAs have been studied to evaluate their functions and possible role in cancer pathogenesis. Small non-coding RNAs are short RNA molecules involved in several cellular processes by regulating the expression of genes. An increasing body of evidence collected by many independent studies shows that the expression of these molecules is tissue specific, and that their dysregulation alters the expression of genes involved in tumor development, progression and drug response. Indeed, small non-coding RNAs play a pivotal role in the onset, staging, relapse and drug response of hematological malignancies and cancers in general. These findings strongly suggest that small non-coding RNAs could function as biomarkers and possible targets for therapy. Thus, in this review, we summarize the regulatory mechanisms of small non-coding RNA expression in different types of leukemia and assess their potential clinical implications. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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16 pages, 850 KiB

Open AccessReview

miRNA- and lncRNA-Based Therapeutics for Non-Hodgkin’s Lymphoma: Moving towards an RNA-Guided Precision Medicine

by Mara Fernandes, Herlander Marques, Ana Luísa Teixeira and Rui Medeiros

Cancers 2021, 13(24), 6324; https://doi.org/10.3390/cancers13246324 - 16 Dec 2021

Cited by 3 | Viewed by 2390

Abstract

Increasing evidence has demonstrated the functional roles of miRNAs and lncRNAs in lymphoma onset and progression, either by acting as tumor-promoting ncRNAs or as tumor suppressors, emphasizing their appeal as lymphoma therapeutics. In fact, their intrinsic ability to modulate multiple dysregulated genes and/or [...] Read more.

Increasing evidence has demonstrated the functional roles of miRNAs and lncRNAs in lymphoma onset and progression, either by acting as tumor-promoting ncRNAs or as tumor suppressors, emphasizing their appeal as lymphoma therapeutics. In fact, their intrinsic ability to modulate multiple dysregulated genes and/or signaling pathways makes them an attractive therapeutic approach for a multifactorial pathology like lymphoma. Currently, the clinical application of miRNA- and lncRNA-based therapies still faces obstacles regarding effective delivery systems, off-target effects, and safety, which can be minimized with the appropriate chemical modifications and the development of tumor site-specific delivery approaches. Moreover, miRNA- and lncRNA-based therapeutics are being studied not only as monotherapies but also as complements of standard treatment regimens to provide a synergic effect, improving the overall treatment efficacy and reducing the therapeutic resistance. In this review, we summarize the fundamentals of miRNA- and lncRNA-based therapeutics by discussing the different types of delivery systems, with a focus on those that have been investigated in lymphoma in vitro and in vivo. Moreover, we described the ongoing clinical trials of novel miRNA- and lncRNA-based therapeutics in lymphoma. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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21 pages, 1537 KiB

Open AccessFeature PaperReview

New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer

by Giulia Fontemaggi, Chiara Turco, Gabriella Esposito and Silvia Di Agostino

Cancers 2021, 13(13), 3154; https://doi.org/10.3390/cancers13133154 - 24 Jun 2021

Cited by 46 | Viewed by 3475

Abstract

Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved [...] Read more.

Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein–protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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31 pages, 2286 KiB

Open AccessReview

Decoding LncRNAs

by Lidia Borkiewicz, Joanna Kalafut, Karolina Dudziak, Alicja Przybyszewska-Podstawka and Ilona Telejko

Cancers 2021, 13(11), 2643; https://doi.org/10.3390/cancers13112643 - 27 May 2021

Cited by 23 | Viewed by 3289

Abstract

Non-coding RNAs (ncRNAs) have been considered as unimportant additions to the transcriptome. Yet, in light of numerous studies, it has become clear that ncRNAs play important roles in development, health and disease. Long-ignored, long non-coding RNAs (lncRNAs), ncRNAs made of more than 200 [...] Read more.

Non-coding RNAs (ncRNAs) have been considered as unimportant additions to the transcriptome. Yet, in light of numerous studies, it has become clear that ncRNAs play important roles in development, health and disease. Long-ignored, long non-coding RNAs (lncRNAs), ncRNAs made of more than 200 nucleotides have gained attention due to their involvement as drivers or suppressors of a myriad of tumours. The detailed understanding of some of their functions, structures and interactomes has been the result of interdisciplinary efforts, as in many cases, new methods need to be created or adapted to characterise these molecules. Unlike most reviews on lncRNAs, we summarize the achievements on lncRNA studies by taking into consideration the approaches for identification of lncRNA functions, interactomes, and structural arrangements. We also provide information about the recent data on the involvement of lncRNAs in diseases and present applications of these molecules, especially in medicine. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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16 pages, 1271 KiB

Open AccessReview

Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective

by Elisa Taiana, Maria Eugenia Gallo Cantafio, Vanessa Katia Favasuli, Cecilia Bandini, Giuseppe Viglietto, Roberto Piva, Antonino Neri and Nicola Amodio

Cancers 2021, 13(9), 2127; https://doi.org/10.3390/cancers13092127 - 28 Apr 2021

Cited by 8 | Viewed by 2191

Abstract

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor [...] Read more.

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor cells to accumulate a wide repertoire of genetic alterations. Such alterations can even be detected at the premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) and, overall, contribute to the acquisition of the malignant traits underlying disease progression. The molecular basis of GI remains unclear, with replication stress and deregulation of DNA damage repair pathways representing the most documented mechanisms. The discovery that non-coding RNA molecules are deeply dysregulated in MM and can target pivotal components of GI pathways has introduced a further layer of complexity to the GI scenario in this disease. In this review, we will summarize available information on the molecular determinants of GI in MM, focusing on the role of non-coding RNAs as novel means to tackle GI for therapeutic intervention. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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27 pages, 1095 KiB

Open AccessEditor’s ChoiceReview

miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy

by Maria Teresa Di Martino, Caterina Riillo, Francesca Scionti, Katia Grillone, Nicoletta Polerà, Daniele Caracciolo, Mariamena Arbitrio, Pierosandro Tagliaferri and Pierfrancesco Tassone

Cancers 2021, 13(7), 1587; https://doi.org/10.3390/cancers13071587 - 30 Mar 2021

Cited by 48 | Viewed by 4952

Abstract

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure [...] Read more.

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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24 pages, 811 KiB

Open AccessReview

The Role of Non-Coding RNAs as Prognostic Factor, Predictor of Drug Response or Resistance and Pharmacological Targets, in the Cutaneous Squamous Cell Carcinoma

by Marianna Garofoli, Mariateresa Volpicella, Michele Guida, Letizia Porcelli and Amalia Azzariti

Cancers 2020, 12(9), 2552; https://doi.org/10.3390/cancers12092552 - 08 Sep 2020

Cited by 16 | Viewed by 2810

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the most common keratinocyte-derived skin cancer in the Caucasian population. Exposure to UV radiations (UVRs) represents the main risk carcinogenesis, causing a considerable accumulation of DNA damage in epidermal keratinocytes with an uncontrolled hyperproliferation and tumor development. [...] Read more.

Cutaneous squamous cell carcinoma (CSCC) is the most common keratinocyte-derived skin cancer in the Caucasian population. Exposure to UV radiations (UVRs) represents the main risk carcinogenesis, causing a considerable accumulation of DNA damage in epidermal keratinocytes with an uncontrolled hyperproliferation and tumor development. The limited and rarely durable response of CSCC to the current therapeutic options has led researchers to look for new therapeutic strategies. Recently, the multi-omics approaches have contributed to the identification and prediction of the key role of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), circularRNAs (circRNAs) and long non-coding RNAs (lncRNAs) in the regulation of several cellular processes in different tumor types, including CSCC. ncRNAs can modulate transcriptional and post-transcriptional events by interacting either with each other or with DNA and proteins, such as transcription factors and RNA-binding proteins. In this review, the implication of ncRNAs in tumorigenesis and their potential role as diagnostic biomarkers and therapeutic targets in human CSCC are reported. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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21 pages, 2384 KiB

Open AccessReview

Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions

by Meysam Sarshar, Daniela Scribano, Cecilia Ambrosi, Anna Teresa Palamara and Andrea Masotti

Cancers 2020, 12(8), 2174; https://doi.org/10.3390/cancers12082174 - 05 Aug 2020

Cited by 34 | Viewed by 5895

Abstract

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and [...] Read more.

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as “messenger” molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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26 pages, 1230 KiB

Open AccessReview

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

by Mohammad Taheri, Hamed Shoorei, Marcel E. Dinger and Soudeh Ghafouri-Fard

Cancers 2020, 12(8), 2162; https://doi.org/10.3390/cancers12082162 - 04 Aug 2020

Cited by 23 | Viewed by 3173

Abstract

Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates [...] Read more.

Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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