The role of alternative splicing in cancer: From oncogenesis to drug resistance

Sciarrillo, Rocco; Wojtuszkiewicz, Anna; Assaraf, Yehuda G.; Jansen, Gerrit; Kaspers, Gertjan J. L.; Giovannetti, Elisa; Cloos, Jacqueline

doi:10.1016/j.drup.2020.100728

Cited by 152 publications

(129 citation statements)

References 248 publications

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“…The AS events also influenced p53 expression in NSCLC and MDM2-B, an AS product of MDM2, was able to promote p53-independent cell growth and inhibition of apoptosis (Coomer et al, 2019). In this regard, the AS events are important in NSCLC development and progression (Bonnal et al, 2020;Sciarrillo et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Zhao

Cai

Zhang

et al. 2021

Front. Mol. Biosci.

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Aberrant N6-methyladenosine (m6A) RNA methylation regulatory genes and related gene alternative splicing (AS) could be used to predict the prognosis of non–small cell lung carcinoma. This study focused on 13 m6A regulatory genes (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, FTO, and ALKBH5) and expression profiles in TCGA-LUAD (n = 504) and TCGA-LUSC (n = 479) datasets from the Cancer Genome Atlas database. The data were downloaded and bioinformatically and statistically analyzed, including the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 43,948 mRNA splicing events in lung adenocarcinoma (LUAD) and 46,020 in lung squamous cell carcinoma (LUSC), and the data suggested that m6A regulators could regulate mRNA splicing. Differential HNRNPC and RBM15 expression was associated with overall survival (OS) of LUAD and HNRNPC and METTL3 expression with the OS of LUSC patients. Furthermore, the non–small cell lung cancer prognosis-related AS events signature was constructed and divided patients into high- vs. low-risk groups using seven and 14 AS genes in LUAD and LUSC, respectively. The LUAD risk signature was associated with gender and T, N, and TNM stages, but the LUSC risk signature was not associated with any clinical features. In addition, the risk signature and TNM stage were independent prognostic predictors in LUAD and the risk signature and T stage were independent prognostic predictors in LUSC after the multivariate Cox regression and receiver operating characteristic analyses. In conclusion, this study revealed the AS prognostic signature in the prediction of LUAD and LUSC prognosis.

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Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Zhao

Cai

Zhang

et al. 2021

Front. Mol. Biosci.

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“…In support of this notion, EZH2 aberrations in acute myeloid leukemia (AML) may be in fact three times more frequent if we consider inactivation due to AS [ 191 ]. The role of AS of oncogenes and tumor suppressors as well as particular splice factor mutations for leukemogenesis are widely-recognized [ 192 , 193 ]. Even though most of these mutations are not studied functionally and remain of unknown impact, many genetic aberrations in splicing factors correlate with poor survival rates.…”

Section: Hematologic Malignanciesmentioning

confidence: 99%

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

Mehterov

Kazakova

Sbirkov

et al. 2021

Genes

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Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.

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“…RNA splicing and alternative splicing are crucial steps in protein expression and the isoforms of the proteins that are expressed by a certain gene are determined by these processes [8]. In cancer, these processes can be altered and this alteration can drive carcinogenesis [60]. In fact, in many types of cancer, splicing factors are either mutated or overexpressed, which strongly indicates an aberrant splicing process in cancer [8,15].…”

Section: Splicing Factors and Alternative Splicing In Pdacmentioning

confidence: 99%

Interrelationship between miRNA and splicing factors in pancreatic ductal adenocarcinoma

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of diagnosis at late stage and inherent/acquired chemoresistance. Recent advances in genomic profiling and biology of this disease have not yet been translated to a relevant improvement in terms of disease management and patient's survival. However, new possibilities for treatment may emerge from studies on key epigenetic factors. Deregulation of microRNA (miRNA) dependent gene expression and mRNA splicing are epigenetic processes that modulate the protein repertoire at the transcriptional level. These processes affect all aspects of PDAC pathogenesis and have great potential to unravel new therapeutic targets and/or biomarkers. Remarkably, several studies showed that they actually interact with each other in influencing PDAC progression. Some splicing factors directly interact with specific miRNAs and either facilitate or inhibit their expression, such as Rbfox2, which cleaves the well-known oncogenic miRNA miR-21. Conversely, miR-15a-5p and miR-25-3p significantly downregulate the splicing factor hnRNPA1 which acts also as a tumour suppressor gene and is involved in processing of miR-18a, which in turn, is a negative regulator of KRAS expression. Therefore, this review describes the interaction between splicing and miRNA, as well as bioinformatic tools to explore the effect of splicing modulation towards miRNA profiles, in order to exploit this interplay for the development of innovative treatments. Targeting aberrant splicing and deregulated miRNA, alone or in combination, may hopefully provide novel therapeutic approaches to fight the complex biology and the common treatment recalcitrance of PDAC.

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The role of alternative splicing in cancer: From oncogenesis to drug resistance

Cited by 152 publications

References 248 publications

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

Interrelationship between miRNA and splicing factors in pancreatic ductal adenocarcinoma

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