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20 pages, 2375 KiB

Open AccessArticle

lncRNAs–mRNAs Co–Expression Network Underlying Childhood B–Cell Acute Lymphoblastic Leukaemia: A Pilot Study

by Ornella Affinito, Katia Pane, Giovanni Smaldone, Francesca Maria Orlandella, Peppino Mirabelli, Giuliana Beneduce, Rosanna Parasole, Mimmo Ripaldi, Marco Salvatore and Monica Franzese

Cancers 2020, 12(9), 2489; https://doi.org/10.3390/cancers12092489 - 02 Sep 2020

Cited by 14 | Viewed by 4056

Abstract

Long non–coding RNAs (lncRNAs) are emerging as key gene regulators in the pathogenesis and development of various cancers including B lymphoblastic leukaemia (B–ALL). In this pilot study, we used RNA–Seq transcriptomic data for identifying novel lncRNA–mRNA cooperative pairs involved in childhood B–ALL pathogenesis. [...] Read more.

Long non–coding RNAs (lncRNAs) are emerging as key gene regulators in the pathogenesis and development of various cancers including B lymphoblastic leukaemia (B–ALL). In this pilot study, we used RNA–Seq transcriptomic data for identifying novel lncRNA–mRNA cooperative pairs involved in childhood B–ALL pathogenesis. We conceived a bioinformatic pipeline based on unsupervised PCA feature extraction approach and stringent statistical criteria to extract potential childhood B–ALL lncRNA signatures. We then constructed a co–expression network of the aberrantly expressed lncRNAs (30) and protein–coding genes (754). We cross–validated our in–silico findings on an independent dataset and assessed the expression levels of the most differentially expressed lncRNAs and their co–expressed mRNAs through ex vivo experiments. Using the guilt–by–association approach, we predicted lncRNA functions based on their perfectly co–expressed mRNAs (Spearman’s correlation) that resulted closely disease–associated. We shed light on 24 key lncRNAs and their co–expressed mRNAs which may play an important role in B–ALL pathogenesis. Our results may be of clinical utility for diagnostic and/or prognostic purposes in paediatric B–ALL management. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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23 pages, 1285 KiB

Open AccessArticle

Comprehensive Analysis of LincRNAs in Classical and Basal-Like Subtypes of Pancreatic Cancer

by Markus Glaß, Agnes Dorn, Stefan Hüttelmaier, Monika Haemmerle and Tony Gutschner

Cancers 2020, 12(8), 2077; https://doi.org/10.3390/cancers12082077 - 27 Jul 2020

Cited by 7 | Viewed by 3362

Abstract

Pancreatic ductal adenocarcinomas (PDAC) belong to the deadliest malignancies in the western world. Mutations in TP53 and KRAS genes along with some other frequent polymorphisms occur almost universally and are major drivers of tumour initiation. However, these mutations cannot explain the heterogeneity in [...] Read more.

Pancreatic ductal adenocarcinomas (PDAC) belong to the deadliest malignancies in the western world. Mutations in TP53 and KRAS genes along with some other frequent polymorphisms occur almost universally and are major drivers of tumour initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses and differences in overall survival observed in PDAC patients. Thus, recent classifications of PDAC tumour samples have leveraged transcriptome-wide gene expression data to account for epigenetic, transcriptional and post-transcriptional mechanisms that may contribute to this deadly disease. Intriguingly, long intervening RNAs (lincRNAs) are a special class of long non-coding RNAs (lncRNAs) that can control gene expression programs on multiple levels thereby contributing to cancer progression. However, their subtype-specific expression and function as well as molecular interactions in PDAC are not fully understood yet. In this study, we systematically investigated the expression of lincRNAs in pancreatic cancer and its molecular subtypes using publicly available data from large-scale studies. We identified 27 deregulated lincRNAs that showed a significant different expression pattern in PDAC subtypes suggesting context-dependent roles. We further analyzed these lincRNAs regarding their common expression patterns. Moreover, we inferred clues on their functions based on correlation analyses and predicted interactions with RNA-binding proteins, microRNAs, and mRNAs. In summary, we identified several PDAC-associated lincRNAs of prognostic relevance and potential context-dependent functions and molecular interactions. Hence, our study provides a valuable resource for future investigations to decipher the role of lincRNAs in pancreatic cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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20 pages, 7423 KiB

Open AccessArticle

Enhancement of Breast Cancer Cell Aggressiveness by lncRNA H19 and its Mir-675 Derivative: Insight into Shared and Different Actions

by Evodie Peperstraete, Clément Lecerf, Jordan Collette, Constance Vennin, Ludivine Raby, Pamela Völkel, Pierre-Olivier Angrand, Marie Winter, François Bertucci, Pascal Finetti, Chann Lagadec, Samuel Meignan, Roland P. Bourette, Xuefen Le Bourhis and Eric Adriaenssens

Cancers 2020, 12(7), 1730; https://doi.org/10.3390/cancers12071730 - 29 Jun 2020

Cited by 24 | Viewed by 3485

Abstract

Breast cancer is a major public health problem and the leading world cause of women death by cancer. Both the recurrence and mortality of breast cancer are mainly caused by the formation of metastasis. The long non-coding RNA H19, the precursor of [...] Read more.

Breast cancer is a major public health problem and the leading world cause of women death by cancer. Both the recurrence and mortality of breast cancer are mainly caused by the formation of metastasis. The long non-coding RNA H19, the precursor of miR-675, is involved in breast cancer development. The aim of this work was to determine the implication but, also, the relative contribution of H19 and miR-675 to the enhancement of breast cancer metastatic potential. We showed that both H19 and miR-675 increase the invasive capacities of breast cancer cells in xenografted transgenic zebrafish models. In vitro, H19 and miR-675 enhance the cell migration and invasion, as well as colony formation. H19 seems to induce the epithelial-to-mesenchymal transition (EMT), with a decreased expression of epithelial markers and an increased expression of mesenchymal markers. Interestingly, miR-675 simultaneously increases the expression of both epithelial and mesenchymal markers, suggesting the induction of a hybrid phenotype or mesenchymal-to-epithelial transition (MET). Finally, we demonstrated for the first time that miR-675, like its precursor H19, increases the stemness properties of breast cancer cells. Altogether, our data suggest that H19 and miR-675 could enhance the aggressiveness of breast cancer cells through both common and different mechanisms. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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22 pages, 4814 KiB

Open AccessArticle

Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains

by Loredana Guglielmi, Marta Nardella, Carla Musa, Ingrid Cifola, Manuela Porru, Beatrice Cardinali, Ilaria Iannetti, Chiara Di Pietro, Giulia Bolasco, Valentina Palmieri, Laura Vilardo, Nicolò Panini, Fabrizio Bonaventura, Massimiliano Papi, Ferdinando Scavizzi, Marcello Raspa, Carlo Leonetti, Germana Falcone, Armando Felsani and Igea D’Agnano

Cancers 2020, 12(6), 1635; https://doi.org/10.3390/cancers12061635 - 19 Jun 2020

Cited by 8 | Viewed by 2690

Abstract

The identification of liquid biomarkers remains a major challenge to improve the diagnosis of melanoma patients with brain metastases. Circulating miRNAs packaged into tumor-secreted small extracellular vesicles (sEVs) contribute to tumor progression. To investigate the release of tumor-secreted miRNAs by brain metastasis, we [...] Read more.

The identification of liquid biomarkers remains a major challenge to improve the diagnosis of melanoma patients with brain metastases. Circulating miRNAs packaged into tumor-secreted small extracellular vesicles (sEVs) contribute to tumor progression. To investigate the release of tumor-secreted miRNAs by brain metastasis, we developed a xenograft model where human metastatic melanoma cells were injected intracranially in nude mice. The comprehensive profiles of both free miRNAs and those packaged in sEVs secreted by the melanoma cells in the plasma demonstrated that most (80%) of the sEV-associated miRNAs were also present in serum EVs from a cohort of metastatic melanomas, included in a publicly available dataset. Remarkably, among them, we found three miRNAs (miR-224-5p, miR-130a-3p and miR-21-5p) in sEVs showing a trend of upregulation during melanoma progression. Our model is proven to be valuable for identifying miRNAs in EVs that are unequivocally secreted by melanoma cells in the brain and could be associated to disease progression. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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23 pages, 4821 KiB

Open AccessArticle

DSCAM-AS1-Driven Proliferation of Breast Cancer Cells Involves Regulation of Alternative Exon Splicing and 3′-End Usage

by Jamal Elhasnaoui, Valentina Miano, Giulio Ferrero, Elena Doria, Antonette E. Leon, Aline S. C. Fabricio, Laura Annaratone, Isabella Castellano, Anna Sapino and Michele De Bortoli

Cancers 2020, 12(6), 1453; https://doi.org/10.3390/cancers12061453 - 03 Jun 2020

Cited by 17 | Viewed by 3646

Abstract

DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B, and HER2-positive Breast Carcinoma (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). DSCAM-AS1 expression is analyzed in 30 public datasets and, additionally, by qRT-PCR [...] Read more.

DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B, and HER2-positive Breast Carcinoma (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). DSCAM-AS1 expression is analyzed in 30 public datasets and, additionally, by qRT-PCR in tumors from 93 BC patients, to uncover correlations with clinical data. Moreover, the effect of DSCAM-AS1 knockdown on gene expression and alternative splicing is studied by RNA-Seq in MCF-7 cells. We confirm DSCAM-AS1 overexpression in high grade Luminal A, B, and HER2+ BCs and find a significant correlation with disease relapse. In total, 908 genes are regulated by DSCAM-AS1-silencing, primarily involved in the cell cycle and inflammatory response. Noteworthily, the analysis of alternative splicing and isoform regulation reveals 2085 splicing events regulated by DSCAM-AS1, enriched in alternative polyadenylation sites, 3′UTR (untranslated region) shortening and exon skipping events. Finally, the DSCAM-AS1-interacting splicing factor heterogeneous nuclear ribonucleoprotein L (hnRNPL) is predicted as the most enriched RBP for exon skipping and 3′UTR events. The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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27 pages, 5063 KiB

Open AccessArticle

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

by Agnes Dorn, Markus Glaß, Carolin T. Neu, Beate Heydel, Stefan Hüttelmaier, Tony Gutschner and Monika Haemmerle

Cancers 2020, 12(5), 1227; https://doi.org/10.3390/cancers12051227 - 13 May 2020

Cited by 19 | Viewed by 4080

Abstract

Pancreatic adenocarcinoma (PDAC) is one of the major causes of cancer-associated deaths worldwide, with a dismal prognosis that has not significantly changed over the last decades. Transcriptional analysis has provided valuable insights into pancreatic tumorigenesis. Specifically, pancreatic cancer subtypes were identified, characterized by [...] Read more.

Pancreatic adenocarcinoma (PDAC) is one of the major causes of cancer-associated deaths worldwide, with a dismal prognosis that has not significantly changed over the last decades. Transcriptional analysis has provided valuable insights into pancreatic tumorigenesis. Specifically, pancreatic cancer subtypes were identified, characterized by specific mutations and gene expression changes associated with differences in patient survival. In addition to differentially regulated mRNAs, non-coding RNAs, including long non-coding RNAs (lncRNAs), were shown to have subtype-specific expression patterns. Hence, we aimed to characterize prognostic lncRNAs with deregulated expression in the squamous subtype of PDAC, which has the worst prognosis. Extensive in silico analyses followed by in vitro experiments identified long intergenic non-coding RNA 261 (LINC00261) as a downregulated lncRNA in the squamous subtype of PDAC, which is generally associated with transforming growth factor β (TGFβ) signaling in human cancer cells. Its genomic neighbor, the transcription factor forkhead box protein A2 (FOXA2), regulated LINC00261 expression by direct binding of the LINC00261 promoter. CRISPR-mediated knockdown and promoter knockout validated the importance of LINC00261 in TGFβ-mediated epithelial–mesenchymal transition (EMT) and established the epithelial marker E-cadherin, an important cell adhesion protein, as a downstream target of LINC00261. Consequently, depletion of LINC00261 enhanced motility and invasiveness of PANC-1 cells in vitro. Altogether, our data suggest that LINC00261 is an important tumor-suppressive lncRNA in PDAC that is involved in maintaining a pro-epithelial state associated with favorable disease outcome. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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17 pages, 2377 KiB

Open AccessArticle

Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer

by Maximilian Seles, Georg C. Hutterer, Johannes Foßelteder, Marek Svoboda, Margit Resel, Dominik A. Barth, Renate Pichler, Thomas Bauernhofer, Richard E. Zigeuner, Karl Pummer, Ondrej Slaby, Christiane Klec and Martin Pichler

Cancers 2020, 12(5), 1200; https://doi.org/10.3390/cancers12051200 - 10 May 2020

Cited by 14 | Viewed by 3392

Abstract

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was [...] Read more.

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts (p < 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort (n = 175, hazard ratio: 4.3, 95% confidence interval: 1.45–12.75, p = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort (n = 530, hazard ratio: 2.19, 95% confidence interval: 1.59–3.03, p ≤ 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration (p < 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A R = 0.19, p < 0.0001, for LAMC2 R = 0.13, p = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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10 pages, 2477 KiB

Open AccessArticle

RNA Editing Alters miRNA Function in Chronic Lymphocytic Leukemia

by Franz J. Gassner, Nadja Zaborsky, Daniel Feldbacher, Richard Greil and Roland Geisberger

Cancers 2020, 12(5), 1159; https://doi.org/10.3390/cancers12051159 - 05 May 2020

Cited by 11 | Viewed by 2941

Abstract

Chronic lymphocytic leukemia (CLL) is a high incidence B cell leukemia with a highly variable clinical course, leading to survival times ranging from months to several decades. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression levels of genes by binding to [...] Read more.

Chronic lymphocytic leukemia (CLL) is a high incidence B cell leukemia with a highly variable clinical course, leading to survival times ranging from months to several decades. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression levels of genes by binding to the untranslated regions of transcripts. Although miRNAs have been previously shown to play a crucial role in CLL development, progression and treatment resistance, their further processing and diversification by RNA editing (specifically adenosine to inosine or cytosine to uracil deamination) has not been addressed so far. In this study, we analyzed next generation sequencing data to provide a detailed map of adenosine to inosine and cytosine to uracil changes in miRNAs from CLL and normal B cells. Our results reveal that in addition to a CLL-specific expression pattern, there is also specific RNA editing of many miRNAs, particularly miR-3157 and miR-6503, in CLL. Our data draw further light on how miRNAs and miRNA editing might be implicated in the pathogenesis of the disease. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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15 pages, 2631 KiB

Open AccessArticle

Increased Level of Long Non-Coding RNA MALAT1 Is a Common Feature of Amoeboid Invasion

by Ladislav Merta, Aneta Gandalovičová, Vladimír Čermák, Michal Dibus, Tony Gutschner, Sven Diederichs, Daniel Rösel and Jan Brábek

Cancers 2020, 12(5), 1136; https://doi.org/10.3390/cancers12051136 - 01 May 2020

Cited by 4 | Viewed by 2930

Abstract

The ability of cancer cells to adopt various migration modes (the plasticity of cancer cell invasiveness) is a substantive obstacle in the treatment of metastasis, yet still an incompletely understood process. We performed a comparison of publicly available transcriptomic datasets from various cell [...] Read more.

The ability of cancer cells to adopt various migration modes (the plasticity of cancer cell invasiveness) is a substantive obstacle in the treatment of metastasis, yet still an incompletely understood process. We performed a comparison of publicly available transcriptomic datasets from various cell types undergoing a switch between the mesenchymal and amoeboid migration modes. Strikingly, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was one of three genes that were found upregulated in all amoeboid cells analyzed. Accordingly, downregulation of MALAT1 in predominantly amoeboid cell lines A375m2 and A2058 resulted in decrease of active RhoA (Ras homolog family member A) and was accompanied by the amoeboid-mesenchymal transition in A375m2 cells. Moreover, MALAT1 downregulation in amoeboid cells led to increased cell proliferation. Our work is the first to address the role of MALAT1 in MAT/AMT (mesenchymal to amoeboid transition/amoeboid to mesenchymal transition) and suggests that increased MALAT1 expression is a common feature of amoeboid cells. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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28 pages, 7361 KiB

Open AccessArticle

The Circular RNA Landscape of Non-Small Cell Lung Cancer Cells

by Nele Van Der Steen, Yanhong Lyu, Anne K. Hitzler, Andrea C. Becker, Jeanette Seiler and Sven Diederichs

Cancers 2020, 12(5), 1091; https://doi.org/10.3390/cancers12051091 - 28 Apr 2020

Cited by 24 | Viewed by 4414

Abstract

The class of circular RNA (circRNA) is characterized by head-to-tail bonds between exons formed by backsplicing. Here, we provide a resource of circRNA expression in a comprehensive panel of 60 lung cancer and non-transformed cell lines (FL3C dataset). RNA sequencing after depletion of [...] Read more.

The class of circular RNA (circRNA) is characterized by head-to-tail bonds between exons formed by backsplicing. Here, we provide a resource of circRNA expression in a comprehensive panel of 60 lung cancer and non-transformed cell lines (FL3C dataset). RNA sequencing after depletion of ribosomal RNA quantified the expression of circRNA and linear RNA. We detected 148,811 circular RNAs quantified by 2.8 million backsplicing reads originating from 12,251 genes. The number of identified circRNAs was markedly higher using rRNA depletion compared to public polyA-enriched RNA-seq datasets. CircRNAs almost never started in the first exon nor ended in the last exon and started more frequently in earlier exons. Most circRNAs showed high cell line specificity and correlated positively with their linear RNA counterpart. Known cancer genes produced more circRNAs than non-cancer genes. Subsets of circRNAs correlated with cell proliferation, histological subtype or genotype. CircTNFRSF21 was translated crossing the backsplice site in two different reading frames. Overexpression of circPVT1, circERBB2, circHIPK3, circCCNB1, circSMAD2, circTNFRSF21 and circKIF5B significantly increased colony formation. In conclusion, our data provide a comprehensive map of circRNA expression in lung cancer cells and global patterns of circRNA production as a useful resource for future research into lung cancer circRNAs. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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14 pages, 4021 KiB

Open AccessArticle

LINC00963 Promotes Cancer Stemness, Metastasis, and Drug Resistance in Head and Neck Carcinomas via ABCB5 Regulation

by Shiao-Pieng Lee, Pei-Ling Hsieh, Chih-Yuan Fang, Pei-Ming Chu, Yi-Wen Liao, Chuan-Hang Yu, Cheng-Chia Yu and Lo-Lin Tsai

Cancers 2020, 12(5), 1073; https://doi.org/10.3390/cancers12051073 - 26 Apr 2020

Cited by 33 | Viewed by 2976

Abstract

Accumulating studies have indicated that long non-coding RNAs (lncRNAs) participate in the regulation of cancer stem cells (CSCs), which are crucial in tumor initiation, metastasis, relapse, and therapy resistance. In the current study, RT-PCR analysis was employed to evaluate the expression of LINC00963 [...] Read more.

Accumulating studies have indicated that long non-coding RNAs (lncRNAs) participate in the regulation of cancer stem cells (CSCs), which are crucial in tumor initiation, metastasis, relapse, and therapy resistance. In the current study, RT-PCR analysis was employed to evaluate the expression of LINC00963 in tumor tissues and oral CSCs. Stemness phenotypes and the expression of CSCs markers in oral cancer cells transfected with sh-LINC00963 were examined. Our results showed that the expression of the lncRNA LINC00963 was up-regulated in oral cancer tissues and CSCs. We found that the downregulation of LINC00963 inhibited CSC hallmarks, such as migration, invasion and colony formation capacity. Moreover, suppression of LINC00963 reduced the activity of stemness marker ALDH1, the percentage of self-renewal, chemoresistance and the expression of multidrug-resistance transporter ABCB5. Most importantly, we demonstrated that knockdown of LINC00963 decreased self-renewal, invasion and colony formation ability via ABCB5. Analysis of TCGA (the Cancer Genome Atlas) datasets suggested that the level of LINC00963 was positively correlated with the expression of the cancer stemness markers (Sox2 and CD44) and drug resistance markers (ABCG2 and ABCB5). Altogether, our results showed that suppression of LINC00963 may be beneficial to inhibit chemoresistance and cancer relapse in oral cancer patients. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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14 pages, 7476 KiB

Open AccessArticle

Oxaliplatin-Induced DHX9 Phosphorylation Promotes Oncogenic Circular RNA CCDC66 Expression and Development of Chemoresistance

by Ya-Chi Lin, Ya-Shan Yu, Hui-Hsuan Lin and Kuei-Yang Hsiao

Cancers 2020, 12(3), 697; https://doi.org/10.3390/cancers12030697 - 16 Mar 2020

Cited by 47 | Viewed by 4446

Abstract

Circular RNA (circRNA), generated through backsplicing in which the downstream splice donor joins the upstream splice acceptor, is a novel class of RNA molecules. Our previous study found that a novel oncogenic circRNA—consisting exon 8–10 of CCDC66—is aberrantly expressed in colorectal cancer [...] Read more.

Circular RNA (circRNA), generated through backsplicing in which the downstream splice donor joins the upstream splice acceptor, is a novel class of RNA molecules. Our previous study found that a novel oncogenic circRNA—consisting exon 8–10 of CCDC66—is aberrantly expressed in colorectal cancer (CRC) tissues and cells. The failure of treatment for colorectal cancer is typically associated with recurrent and chemoresistant cancerous tissues. In this study, we aimed to investigate the role(s) of circCCDC66 during the development of chemoresistance. We discovered that the expression level of circCCDC66 is elevated in colorectal cancer cells with resistance to oxaliplatin. Knockdown of circCCDC66 caused the downregulation of a subset of genes which are regulated by circCCDC66-associated miRNAs and related to the modulation of apoptosis and the cell cycle, suppressing cell survival, promoting oxaliplatin-induced apoptosis and, thus, hindering the development of oxaliplatin-resistance (OxR). The induction of circCCDC66 was dependent on the time-course and dose of oxaliplatin treatment. Our analyses revealed that DHX9 harbors two phosphorylation sites of phosphatidylinositol 3-kinase-related kinases (PI3KKs) close to substrate-binding domains. Blockage of phosphorylation by either PI3KK inhibitors or nonphosphorable mutants of DHX9 decreased the oxaliplatin-induced circCCDC66 expression and the ability to develop chemoresistant cells. Taken together, we demonstrated and linked the functional role of DHX9 phosphorylation to oncogenic circCCDC66 expression during the development of resistance to oxaliplatin, providing a mechanistic insight for the development of therapeutic strategies to recurring/chemoresistant colorectal cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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19 pages, 3300 KiB

Open AccessArticle

Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

by Stefan Hatzl, Bianca Perfler, Sonja Wurm, Barbara Uhl, Franz Quehenberger, Susanne Ebner, Jakob Troppmair, Andreas Reinisch, Albert Wölfler, Heinz Sill and Armin Zebisch

Cancers 2020, 12(2), 496; https://doi.org/10.3390/cancers12020496 - 20 Feb 2020

Cited by 13 | Viewed by 3613

Abstract

Resistance to chemotherapy is one of the primary obstacles in acute myeloid leukemia (AML) therapy. Micro-RNA-23a (miR-23a) is frequently deregulated in AML and has been linked to chemoresistance in solid cancers. We, therefore, studied its role in chemoresistance to cytarabine (AraC), which forms [...] Read more.

Resistance to chemotherapy is one of the primary obstacles in acute myeloid leukemia (AML) therapy. Micro-RNA-23a (miR-23a) is frequently deregulated in AML and has been linked to chemoresistance in solid cancers. We, therefore, studied its role in chemoresistance to cytarabine (AraC), which forms the backbone of all cytostatic AML treatments. Initially, we assessed AraC sensitivity in three AML cell lines following miR-23a overexpression/knockdown using MTT-cell viability and soft-agar colony-formation assays. Overexpression of miR-23a decreased the sensitivity to AraC, whereas its knockdown had the opposite effect. Analysis of clinical data revealed that high miR-23a expression correlated with relapsed/refractory (R/R) AML disease stages, the leukemic stem cell compartment, as well as with inferior overall survival (OS) and event-free survival (EFS) in AraC-treated patients. Mechanistically, we demonstrate that miR-23a targets and downregulates topoisomerase-2-beta (TOP2B), and that TOP2B knockdown mediates AraC chemoresistance as well. Likewise, low TOP2B expression also correlated with R/R-AML disease stages and inferior EFS/OS. In conclusion, we show that increased expression of miR-23a mediates chemoresistance to AraC in AML and that it correlates with an inferior outcome in AraC-treated AML patients. We further demonstrate that miR-23a causes the downregulation of TOP2B, which is likely to mediate its effects on AraC sensitivity. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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18 pages, 10094 KiB

Open AccessArticle

The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma

by Haotian Shen, Lindsay M. Wong, Wei Tse Li, Megan Chu, Rachel A. High, Eric Y. Chang, Jessica Wang-Rodriguez and Weg M. Ongkeko

Cancers 2019, 11(12), 1919; https://doi.org/10.3390/cancers11121919 - 02 Dec 2019

Cited by 4 | Viewed by 2687

Abstract

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential [...] Read more.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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Review

Jump to: Research

29 pages, 422 KiB

Open AccessReview

Cancer of Unknown Primary: Challenges and Progress in Clinical Management

by Noemi Laprovitera, Mattia Riefolo, Elisa Ambrosini, Christiane Klec, Martin Pichler and Manuela Ferracin

Cancers 2021, 13(3), 451; https://doi.org/10.3390/cancers13030451 - 25 Jan 2021

Cited by 19 | Viewed by 5476

Abstract

Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of [...] Read more.

Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3–5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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28 pages, 1307 KiB

Open AccessFeature PaperReview

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

by Dominik A. Barth, Jaroslav Juracek, Ondrej Slaby, Martin Pichler and George A. Calin

Cancers 2020, 12(8), 2148; https://doi.org/10.3390/cancers12082148 - 03 Aug 2020

Cited by 28 | Viewed by 4609

Abstract

Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to [...] Read more.

Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to cancer therapies are yet to enter clinical routine. Long non-coding RNAs (lncRNA) are non-protein coding RNA transcripts longer than 200 nucleotides that exert multiple types of regulatory functions of all known cellular processes. Increasing evidence supports the role of lncRNAs in cancer development and progression. Additionally, their involvement in the development of drug resistance across various cancer entities, including genitourinary malignancies, are starting to be discovered. Consequently, lncRNAs have been suggested as factors in novel therapeutic strategies to overcome drug resistance in cancer. In this review, the existing evidences on lncRNAs and their involvement in mechanisms of drug resistance in cancers of the genitourinary system, including renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer, will be highlighted and discussed to facilitate and encourage further research in this field. We summarize a significant number of lncRNAs with proposed pathways in drug resistance and available reported studies. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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19 pages, 1983 KiB

Open AccessReview

Non-Coding RNA Editing in Cancer Pathogenesis

by Giulia Romano, Michela Saviana, Patricia Le, Howard Li, Lavender Micalo, Giovanni Nigita, Mario Acunzo and Patrick Nana-Sinkam

Cancers 2020, 12(7), 1845; https://doi.org/10.3390/cancers12071845 - 08 Jul 2020

Cited by 16 | Viewed by 3285

Abstract

In the last two decades, RNA post-transcriptional modifications, including RNA editing, have been the subject of increasing interest among the scientific community. The efforts of the Human Genome Project combined with the development of new sequencing technologies and dedicated bioinformatic approaches created to [...] Read more.

In the last two decades, RNA post-transcriptional modifications, including RNA editing, have been the subject of increasing interest among the scientific community. The efforts of the Human Genome Project combined with the development of new sequencing technologies and dedicated bioinformatic approaches created to detect and profile RNA transcripts have served to further our understanding of RNA editing. Investigators have determined that non-coding RNA (ncRNA) A-to-I editing is often deregulated in cancer. This discovery has led to an increased number of published studies in the field. However, the eventual clinical application for these findings remains a work in progress. In this review, we provide an overview of the ncRNA editing phenomenon in cancer. We discuss the bioinformatic strategies for RNA editing detection as well as the potential roles for ncRNA A to I editing in tumor immunity and as clinical biomarkers. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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27 pages, 2588 KiB

Open AccessReview

Non-Coding RNAs in Cancer Radiosensitivity: MicroRNAs and lncRNAs as Regulators of Radiation-Induced Signaling Pathways

by Marta Podralska, Sylwia Ciesielska, Joost Kluiver, Anke van den Berg, Agnieszka Dzikiewicz-Krawczyk and Izabella Slezak-Prochazka

Cancers 2020, 12(6), 1662; https://doi.org/10.3390/cancers12061662 - 23 Jun 2020

Cited by 43 | Viewed by 5369

Abstract

Radiotherapy is a cancer treatment that applies high doses of ionizing radiation to induce cell death, mainly by triggering DNA double-strand breaks. The outcome of radiotherapy greatly depends on radiosensitivity of cancer cells, which is determined by multiple proteins and cellular processes. In [...] Read more.

Radiotherapy is a cancer treatment that applies high doses of ionizing radiation to induce cell death, mainly by triggering DNA double-strand breaks. The outcome of radiotherapy greatly depends on radiosensitivity of cancer cells, which is determined by multiple proteins and cellular processes. In this review, we summarize current knowledge on the role of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in determining the response to radiation. Non-coding RNAs modulate ionizing radiation response by targeting key signaling pathways, including DNA damage repair, apoptosis, glycolysis, cell cycle arrest, and autophagy. Additionally, we indicate miRNAs and lncRNAs that upon overexpression or inhibition alter cellular radiosensitivity. Current data indicate the potential of using specific non-coding RNAs as modulators of cellular radiosensitivity to improve outcome of radiotherapy. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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22 pages, 1416 KiB

Open AccessReview

Challenges and Strategies in Ascribing Functions to Long Noncoding RNAs

by Yang Zhao, Hongqi Teng, Fan Yao, Shannon Yap, Yutong Sun and Li Ma

Cancers 2020, 12(6), 1458; https://doi.org/10.3390/cancers12061458 - 03 Jun 2020

Cited by 35 | Viewed by 4189

Abstract

Long noncoding RNAs (lncRNAs) are involved in many physiological and pathological processes, such as development, aging, immunity, and cancer. Mechanistically, lncRNAs exert their functions through interaction with proteins, genomic DNA, and other RNA, leading to transcriptional and post-transcriptional regulation of gene expression, either [...] Read more.

Long noncoding RNAs (lncRNAs) are involved in many physiological and pathological processes, such as development, aging, immunity, and cancer. Mechanistically, lncRNAs exert their functions through interaction with proteins, genomic DNA, and other RNA, leading to transcriptional and post-transcriptional regulation of gene expression, either in cis or in trans; it is often difficult to distinguish between these two regulatory mechanisms. A variety of approaches, including RNA interference, antisense oligonucleotides, CRISPR-based methods, and genetically engineered mouse models, have yielded abundant information about lncRNA functions and underlying mechanisms, albeit with many discrepancies. In this review, we elaborate on the challenges in ascribing functions to lncRNAs based on the features of lncRNAs, including the genomic location, copy number, domain structure, subcellular localization, stability, evolution, and expression pattern. We also describe a framework for the investigation of lncRNA functions and mechanisms of action. Rigorous characterization of cancer-implicated lncRNAs is critical for the identification of bona fide anticancer targets. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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17 pages, 275 KiB

Open AccessReview

The Long and Short of It: The Emerging Roles of Non-Coding RNA in Small Extracellular Vesicles

by Agata Abramowicz and Michael D Story

Cancers 2020, 12(6), 1445; https://doi.org/10.3390/cancers12061445 - 02 Jun 2020

Cited by 42 | Viewed by 4102

Abstract

Small extracellular vesicles (EVs) play a significant role in intercellular communication through their non-coding RNA (ncRNA) cargo. While the initial examination of EV cargo identified both mRNA and miRNA, later studies revealed a wealth of other types of EV-related non-randomly packed ncRNAs, including [...] Read more.

Small extracellular vesicles (EVs) play a significant role in intercellular communication through their non-coding RNA (ncRNA) cargo. While the initial examination of EV cargo identified both mRNA and miRNA, later studies revealed a wealth of other types of EV-related non-randomly packed ncRNAs, including tRNA and tRNA fragments, Y RNA, piRNA, rRNA, and lncRNA. A number of potential roles for these ncRNA species were suggested, with strong evidence provided in some cases, whereas the role for other ncRNA is more speculative. For example, long non-coding RNA might be used as a potential diagnostic tool but might also mediate resistance to certain cancer-specific chemotherapy agents. piRNAs, on the other hand, have a significant role in genome integrity, however, no role has yet been defined for the piRNAs found in EVs. While our knowledgebase for the function of ncRNA-containing EVs is still modest, the potential role that these EV-ensconced ncRNA might play is promising. This review summarizes the ncRNA content of EVs and describes the function where known, or the potential utility of EVs that harbor specific types of ncRNA. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

21 pages, 1620 KiB

Open AccessReview

Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer

by Toshihiko Takeiwa, Kazuhiro Ikeda, Yuichi Mitobe, Kuniko Horie-Inoue and Satoshi Inoue

Cancers 2020, 12(6), 1424; https://doi.org/10.3390/cancers12061424 - 31 May 2020

Cited by 14 | Viewed by 2767

Abstract

Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs [...] Read more.

Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs have been demonstrated to be involved in endocrine therapy resistance for breast cancer through their own mechanisms, suggesting that lncRNAs could be promising new biomarkers and therapeutic targets of breast cancer. Here, we summarize the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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16 pages, 584 KiB

Open AccessReview

The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma

by Lysann Tietze and Sonja M. Kessler

Cancers 2020, 12(5), 1261; https://doi.org/10.3390/cancers12051261 - 16 May 2020

Cited by 30 | Viewed by 3925

Abstract

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The [...] Read more.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The use of long noncoding (lnc) RNAs can widen the list of novel molecular targets improving cancer therapy. In hepatocarcinogenesis, the role of the lncRNA H19, which has been known for more than 30 years now, is still controversially discussed. H19 was described to work either as a tumor suppressor in vitro and in vivo, or to have oncogenic features. This review attempts to survey the conflicting study results and tries to elucidate the potential reasons for the contrary findings, i.e., different methods, models, or readout parameters. This review encompasses in vitro and in vivo models as well as studies on human patient samples. Although the function of H19 in HCC remains elusive, a short outlook summarizes some ideas of using the H19 locus as a novel target for liver cancer therapy. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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27 pages, 558 KiB

Open AccessReview

Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma

by Debashri Manna and Devanand Sarkar

Cancers 2020, 12(5), 1243; https://doi.org/10.3390/cancers12051243 - 15 May 2020

Cited by 11 | Viewed by 2953

Abstract

Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, is a universal health problem and one of the most common malignant tumors. Surgery followed by chemotherapy as well as tyrosine kinase inhibitors (TKIs), such as sorafenib, are primary treatment procedures for HCC, [...] Read more.

Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, is a universal health problem and one of the most common malignant tumors. Surgery followed by chemotherapy as well as tyrosine kinase inhibitors (TKIs), such as sorafenib, are primary treatment procedures for HCC, but recurrence of disease because of therapy resistance results in high mortality. It is necessary to identify novel regulators of HCC for developing effective targeted therapies that can significantly interfere with progression of the disease process. Non-coding RNAs (ncRNAs) are an abundant group of versatile RNA transcripts that do not translate into proteins, rather serve as potentially functional RNAs. The role of ncRNAs in regulating diverse aspects of the carcinogenesis process are gradually being elucidated. Recent advances in RNA sequencing technology have identified a plethora of ncRNAs regulating all aspects of hepatocarcinogenesis process and serving as potential prognostic or diagnostic biomarkers. The present review provides a comprehensive description of the biological roles of ncRNAs in disease process and therapy resistance, and potential clinical application of these ncRNAs in HCC. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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21 pages, 1365 KiB

Open AccessReview

Y RNA: An Overview of Their Role as Potential Biomarkers and Molecular Targets in Human Cancers

by Caterina Gulìa, Fabrizio Signore, Marco Gaffi, Silvia Gigli, Raffaella Votino, Roberto Nucciotti, Luca Bertacca, Simona Zaami, Alberto Baffa, Edoardo Santini, Alessandro Porrello and Roberto Piergentili

Cancers 2020, 12(5), 1238; https://doi.org/10.3390/cancers12051238 - 14 May 2020

Cited by 19 | Viewed by 5065

Abstract

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years [...] Read more.

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years ago. Since then, only a few contributions were published, mostly scattered across different tumor types and, in some cases, also suffering from methodological limitations. Nonetheless, these sparse data may be used to make some estimations and suggest routes to better understand the role of Y RNA in cancer formation and characterization. Here we summarize the current knowledge about Y RNA in multiple types of cancer, also including a paragraph about tumors that might be included in this list in the future, if more evidence becomes available. The picture arising indicates that Y RNA might be useful in tumor characterization, also relying on non-invasive methods, such as the analysis of the content of extracellular vesicles (EV) that are retrieved from blood plasma and other bodily fluids. Due to the established role of Y RNA in DNA replication, it is possible to hypothesize their therapeutic targeting to inhibit cell proliferation in oncological patients. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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18 pages, 1822 KiB

Open AccessReview

MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas

by Maria Gluud, Andreas Willerslev-Olsen, Lise Mette Rahbek Gjerdrum, Lise M. Lindahl, Terkild B. Buus, Mads Hald Andersen, Charlotte Menne Bonefeld, Thorbjorn Krejsgaard, Ivan V. Litvinov, Lars Iversen, Jürgen C. Becker, Jenny L. Persson, Sergei B. Koralov, Thomas Litman, Carsten Geisler, Anders Woetmann and Niels Odum

Cancers 2020, 12(5), 1229; https://doi.org/10.3390/cancers12051229 - 13 May 2020

Cited by 27 | Viewed by 7815

Abstract

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability [...] Read more.

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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21 pages, 856 KiB

Open AccessReview

Long Non-Coding RNA HOTAIR in Breast Cancer Therapy

by Monica Cantile, Maurizio Di Bonito, Margherita Cerrone, Francesca Collina, Michelino De Laurentiis and Gerardo Botti

Cancers 2020, 12(5), 1197; https://doi.org/10.3390/cancers12051197 - 09 May 2020

Cited by 68 | Viewed by 4683

Abstract

Breast cancer (BC) is the most common cancer type among women, and morbidity and mortality rates are still very high. Despite new innovative therapeutic approaches for all BC molecular subtypes, the discovery of new molecular biomarkers involved in tumor progression has been fundamental [...] Read more.

Breast cancer (BC) is the most common cancer type among women, and morbidity and mortality rates are still very high. Despite new innovative therapeutic approaches for all BC molecular subtypes, the discovery of new molecular biomarkers involved in tumor progression has been fundamental for the implementation of personalized treatment strategies and improvement of patient management. Many experimental studies indicate that long non-coding RNAs (lncRNAs) are strongly involved in BC initiation, metastatic progression, and drug resistance. In particular, aberrant expression of HOX transcript antisense intergenic RNA (HOTAIR) lncRNA plays an important role in BC contributing to its progression and represents a predictor of BC metastasis. For its proven prognostic value, HOTAIR could represent a potential therapeutic target in BC. In the present review, we summarize the role of HOTAIR in cancer progression and drug resistance, in particular in BC, and we illustrate the main approaches for silencing it. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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25 pages, 1630 KiB

Open AccessReview

The Challenges and Opportunities of LncRNAs in Ovarian Cancer Research and Clinical Use

by Martín Salamini-Montemurri, Mónica Lamas-Maceiras, Aida Barreiro-Alonso, Ángel Vizoso-Vázquez, Esther Rodríguez-Belmonte, María Quindós-Varela and María Esperanza Cerdán

Cancers 2020, 12(4), 1020; https://doi.org/10.3390/cancers12041020 - 21 Apr 2020

Cited by 25 | Viewed by 4910

Abstract

Ovarian cancer is one of the most lethal gynecological malignancies worldwide because it tends to be detected late, when the disease has already spread, and prognosis is poor. In this review we aim to highlight the importance of long non-coding RNAs (lncRNAs) in [...] Read more.

Ovarian cancer is one of the most lethal gynecological malignancies worldwide because it tends to be detected late, when the disease has already spread, and prognosis is poor. In this review we aim to highlight the importance of long non-coding RNAs (lncRNAs) in diagnosis, prognosis and treatment choice, to make progress towards increasingly personalized medicine in this malignancy. We review the effects of lncRNAs associated with ovarian cancer in the context of cancer hallmarks. We also discuss the molecular mechanisms by which lncRNAs become involved in cellular physiology; the onset, development and progression of ovarian cancer; and lncRNAs’ regulatory mechanisms at the transcriptional, post-transcriptional and post-translational stages of gene expression. Finally, we compile a series of online resources useful for the study of lncRNAs, especially in the context of ovarian cancer. Future work required in the field is also discussed along with some concluding remarks. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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18 pages, 1187 KiB

Open AccessReview

MicroRNAs as Emerging Regulators of Signaling in the Tumor Microenvironment

by Shahzad Nawaz Syed and Bernhard Brüne

Cancers 2020, 12(4), 911; https://doi.org/10.3390/cancers12040911 - 08 Apr 2020

Cited by 26 | Viewed by 3270

Abstract

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a [...] Read more.

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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16 pages, 612 KiB

Open AccessReview

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

by Manuel Regouc, Gazanfer Belge, Anja Lorch, Klaus-Peter Dieckmann and Martin Pichler

Cancers 2020, 12(3), 749; https://doi.org/10.3390/cancers12030749 - 22 Mar 2020

Cited by 41 | Viewed by 7034

Abstract

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical [...] Read more.

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical procedures and chemotherapeutic treatment provide a high chance of cure in early stages, though some patients in advanced stages belonging to a poor risk group experience cancer-related death. Though conventional serum-based tumor markers, including α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are useful as prognostic and diagnostic biomarkers, unfortunately, these tumor markers only have a sensitivity of about 60%, and in pure seminoma even lower with about 20%. Therefore, the development of new tumor markers is an important and intensively ongoing issue. The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future. miRNAs are small RNAs secreted by testicular tumor cells and circulate and be measurable in body fluids. In recent years, miRNAs of the miR-371-373 cluster in particular have been identified as potentially superior tumor markers in testicular cancer patients. Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue. Several studies including high prospective multi-center trials clearly demonstrated that these miRNAs significantly exceed the sensitivity and specificity of conventional tumor markers and may help to facilitate the diagnosis, follow-up, and early detection of recurrences in testicular cancer patients. In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review. However, further studies are needed to identify the value of these novel markers in additional clinical scenarios, including the monitoring in active surveillance or after adjuvant chemotherapy, but also to show the limitations of these tumor markers. The aim of this review is to give an overview on the current knowledge regarding the relevance of non-coding miRNAs as biomarkers in testicular cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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32 pages, 3686 KiB

Open AccessEditor’s ChoiceReview

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells

by Kirti S. Prabhu, Afsheen Raza, Thasni Karedath, Syed Shadab Raza, Hamna Fathima, Eiman I. Ahmed, Shilpa Kuttikrishnan, Lubna Therachiyil, Michal Kulinski, Said Dermime, Kulsoom Junejo, Martin Steinhoff and Shahab Uddin

Cancers 2020, 12(2), 351; https://doi.org/10.3390/cancers12020351 - 04 Feb 2020

Cited by 35 | Viewed by 5025

Abstract

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a [...] Read more.

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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16 pages, 551 KiB

Open AccessReview

MicroRNAs as Theranostics Targets in Oral Carcinoma Stem Cells

by Pei-Ling Hsieh, Yi-Wen Liao, Martin Pichler and Cheng-Chia Yu

Cancers 2020, 12(2), 340; https://doi.org/10.3390/cancers12020340 - 03 Feb 2020

Cited by 14 | Viewed by 2636

Abstract

Oral cancer belongs to head and neck squamous cell carcinoma and has been recognized as one of the most prevalent malignancies worldwide. Recent studies have suggested that cancer stem cells (CSCs) may participate in tumor initiation, metastasis and even recurrence, so the regulation [...] Read more.

Oral cancer belongs to head and neck squamous cell carcinoma and has been recognized as one of the most prevalent malignancies worldwide. Recent studies have suggested that cancer stem cells (CSCs) may participate in tumor initiation, metastasis and even recurrence, so the regulation of CSCs has drawn significant attention over the past decade. Among various molecules that are associated with CSCs, non-coding RNAs (ncRNAs) have been indicated as key players in the acquisition and maintenance of cancer stemness. In addition, accumulating studies have shown that the aberrant expression of these ncRNAs may serve as surrogate diagnostic markers or even therapeutic targets for cancer treatment. The current study reviews the previous work by us and others to summarize how these ncRNAs affect oral cancer stemness and their potential theranostic applications. A better understanding of the implication of these ncRNAs in oral tumorigenesis will facilitate the translation of basic ncRNA research into clinical application in the future. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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19 pages, 3721 KiB

Open AccessReview

Current Concepts of Non-Coding RNAs in the Pathogenesis of Non-Clear Cell Renal Cell Carcinoma

by Dominik A. Barth, Ondrej Slaby, Christiane Klec, Jaroslav Juracek, Rares Drula, George A. Calin and Martin Pichler

Cancers 2019, 11(10), 1580; https://doi.org/10.3390/cancers11101580 - 17 Oct 2019

Cited by 33 | Viewed by 3740

Abstract

Renal cell carcinoma (RCC) is a relatively rare malignancy of the urinary tract system. RCC is a heterogenous disease in terms of underlying histology and its associated underlying pathobiology, prognosis and treatment schedule. The most prevalent histological RCC subtype is clear-cell renal cell [...] Read more.

Renal cell carcinoma (RCC) is a relatively rare malignancy of the urinary tract system. RCC is a heterogenous disease in terms of underlying histology and its associated underlying pathobiology, prognosis and treatment schedule. The most prevalent histological RCC subtype is clear-cell renal cell carcinoma (ccRCC), accounting for about 70–80% of all RCCs. Though the pathobiology and treatment schedule for ccRCC are well-established, non-ccRCC subtypes account for 20%–30% of RCC altogether, and their underlying molecular biology and treatment options are poorly defined. The class of non-coding RNAs—molecules that are generally not translated into proteins—are new cancer drivers and suppressors in all types of cancer. Of these, small non-coding microRNAs (miRNAs) contribute to carcinogenesis by regulating posttranscriptional gene silencing. Additionally, a growing body of evidence supports the role of long non-coding RNAs (lncRNAs) in cancer development and progression. Most studies on non-coding RNAs in RCC focus on clear-cell histology, and there is a relatively limited number of studies on non-ccRCC subtypes. The aim of this review is to give an overview of the current knowledge regarding the role of non-coding RNAs (including short and long non-coding RNAs) in non-ccRCC and to highlight possible implications as diagnostic, prognostic and predictive biomarkers. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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