scholarly journals Impact of Alternative Splicing Variants on Liver Cancer Biology

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 18
Author(s):  
Jose J. G. Marin ◽  
Maria Reviejo ◽  
Meraris Soto ◽  
Elisa Lozano ◽  
Maitane Asensio ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Survival Rates ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Splicing Variants ◽  
Mrna Maturation ◽  
Available Information ◽  
The Impact

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 130
Author(s):  
Flavia Zita Francies ◽  
Sheynaz Bassa ◽  
Aristotelis Chatziioannou ◽  
Andreas Martin Kaufmann ◽  
Zodwa Dlamini
Keyword(s):  
Cervical Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Molecular Alteration ◽  
Common Cancer ◽  
Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

scholarly journals Insights into Telomerase/hTERT Alternative Splicing Regulation Using Bioinformatics and Network Analysis in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 666 ◽  
Author(s):  
Andrew T. Ludlow ◽  
Aaron L. Slusher ◽  
Mohammed E. Sayed
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Rna Processing ◽  
Splicing Regulation ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Htert Gene ◽  
Splicing Variants ◽  
Cis And Trans ◽  
Telomerase Regulation

The reactivation of telomerase in cancer cells remains incompletely understood. The catalytic component of telomerase, hTERT, is thought to be the limiting component in cancer cells for the formation of active enzymes. hTERT gene expression is regulated at several levels including chromatin, DNA methylation, transcription factors, and RNA processing events. Of these regulatory events, RNA processing has received little attention until recently. RNA processing and alternative splicing regulation have been explored to understand how hTERT is regulated in cancer cells. The cis- and trans-acting factors that regulate the alternative splicing choice of hTERT in the reverse transcriptase domain have been investigated. Further, it was discovered that the splicing factors that promote the production of full-length hTERT were also involved in cancer cell growth and survival. The goals are to review telomerase regulation via alternative splicing and the function of hTERT splicing variants and to point out how bioinformatics approaches are leading the way in elucidating the networks that regulate hTERT splicing choice and ultimately cancer growth.

scholarly journals The Effects of Histone Deacetylase (HDAC) Inhibitors on FASN Intracellular Localization in Cancer Cells

2020 ◽  
Vol 21 (2) ◽  
Author(s):  
Elizabeth Colvin ◽  
Daiqing Liao
Keyword(s):  
Cell Proliferation ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Cancer Biology ◽  
Lipid Production ◽  
Intracellular Localization ◽  
Lipid Synthesis ◽  
Intracellular Location ◽  
The Impact

Understanding mechanisms underlying cancer biology is crucial for discovering novel and effective therapies to improve patient outcome. Increased lipid production is a major metabolic feature in cancer. The fatty acid synthase (FASN) is a key enzyme for lipid synthesis and is upregulated in cancer. Although fatty acid synthesis is generally thought to take place in the cytoplasm, it has been reported that this enzyme also localizes to the nucleus in cancer cells. We hypothesize that the intracellular localization FASN could be a potential target to decrease lipid synthesis and ultimately halt cell proliferation. Protein acetylation has been shown to regulate protein intracellular localization. We aim to assess the impact histone deacetylase inhibitors (HDACi) have on the intracellular location of FASN with the goal of reducing de novo lipid production and cancer cell proliferation. We have examined intracellular localization of FASN in cells using immunofluorescence microscopy in cancer cells treated with HDACi and did not detect obvious HDACi-induced changes in FASN localization. FASN is also regulated by other mechanisms such as phosphorylation. Future studies will examine effects of kinase inhibitors on FASN intracellular localization.

scholarly journals Splicing Programs and Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Sophie Germann ◽  
Lise Gratadou ◽  
Martin Dutertre ◽  
Didier Auboeuf
Keyword(s):  
Alternative Splicing ◽  
Gene Networks ◽  
Large Scale ◽  
Splicing Factors ◽  
Novel Technologies ◽  
Normal Tissues ◽  
Genome Wide ◽  
Splicing Variants ◽  
Cancer Initiation ◽  
Genetic Mechanisms

Numerous studies report splicing alterations in a multitude of cancers by using gene-by-gene analysis. However, understanding of the role of alternative splicing in cancer is now reaching a new level, thanks to the use of novel technologies allowing the analysis of splicing at a large-scale level. Genome-wide analyses of alternative splicing indicate that splicing alterations can affect the products of gene networks involved in key cellular programs. In addition, many splicing variants identified as being misregulated in cancer are expressed in normal tissues. These observations suggest that splicing programs contribute to specific cellular programs that are altered during cancer initiation and progression. Supporting this model, recent studies have identified splicing factors controlling cancer-associated splicing programs. The characterization of splicing programs and their regulation by splicing factors will allow a better understanding of the genetic mechanisms involved in cancer initiation and progression and the development of new therapeutic targets.

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

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1085
Author(s):  
Nikolay Mehterov ◽  
Maria Kazakova ◽  
Yordan Sbirkov ◽  
Boyan Vladimirov ◽  
Nikolay Belev ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Chemotherapeutic Agents ◽  
Human Genes ◽  
Splicing Variants ◽  
Almost All ◽  
Aberrant Rna

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.

BRCA1 exon 11 alternative splicing, multiple functions and the association with cancer

2012 ◽  
Vol 40 (4) ◽  
pp. 768-772 ◽  
Author(s):  
Claudia Tammaro ◽  
Michela Raponi ◽  
David I. Wilson ◽  
Diana Baralle
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Cancer Biology ◽  
Mammary Epithelial Cells ◽  
Splice Variants ◽  
Mammary Epithelial ◽  
Cell Phenotype ◽  
Exon 11 ◽  
The Impact ◽  
Brca1 Exon

BRCA1 (breast cancer early-onset 1) alternative splicing levels are regulated in a cell-cycle- and cell-type-specific manner, with splice variants being present in different proportions in tumour cell lines as well as in normal mammary epithelial cells. The importance of this difference in the pathogenesis of breast cancer has yet to be determined. Developing an understanding of the impact of BRCA1 isoform ratio changes on cell phenotype will be of value in breast cancer and may offer therapeutic options. In the present paper, we describe the splicing isoforms of BRCA1 exon 11, their possible role in cancer biology and the importance of maintaining a balanced ratio.

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

2021 ◽  
Author(s):  
Zhiwu Wang ◽  
Qiong Wu ◽  
Yankun Liu ◽  
Jingwu Li
Keyword(s):  
Gastric Cancer ◽  
Alternative Splicing ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Splicing Factors ◽  
Rna Seq ◽  
Oncogenic Pathways ◽  
Splicing Variants ◽  
Cancer Genome Atlas

Abstract Aberrant alternative splicing (AS) events serve as prognostic indicators in a large number of malignancies, whereas comprehensive analysis of prognostic AS in gastric cancer (GC) has not yet been understood. To identify prognostic AS events and clarify the function of the splicing variants in GC. RNA-Seq data, clinical information and percent spliced in (PSI) values were available in the cancer genome atlas (TCGA) and TCGA SpliceSeq data portal. A three-step regression method was conducted to screen prognostic AS events and construct multi-AS-based signatures. The associations between prognostic AS events and splicing factors were also investigated. We identified a total of 1318 survival related AS events in GC, Parent genes of which were implicated in numerous oncogenic pathways. The final prognostic signatures stratified by seven types of AS events or not stratified performed well in risk prediction for GC patients. Moreover, five signatures base on AA, AD, AT, ES and RI events function as independent prognostic indicators after multivariate adjustment of clinicalpathological variables. Splicing network also showed marked correlation between the expression of splicing factors and PSI value of AS events in GC patients. The AS derived signatures allow to predict GC prognosis and might serve as potential therapeutic target for GC.

scholarly journals Inhibition of Wnt/β-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy

2021 ◽  
Vol 22 (19) ◽  
pp. 10301
Author(s):  
Melanie Spitzner ◽  
Georg Emons ◽  
Karl Burkhard Schütz ◽  
Hendrik A. Wolff ◽  
Stefan Rieken ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Locally Advanced ◽  
Survival Rates ◽  
Treatment Resistance ◽  
Preoperative Chemoradiotherapy ◽  
Wnt Proteins ◽  
Esophageal Cancer Cells ◽  
The Impact

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients’ outcome. In this study, we investigated the impact of Wnt/β-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/β-catenin signaling activities. To investigate the effect of Wnt/β-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/β-catenin signaling. Our experiments revealed that inhibition of Wnt/β-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/β-catenin activity may guide precision therapies in esophageal carcinoma patients.

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