Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities (original) (raw)
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Altered Expression of MBNL Family of Alternative Splicing Factors in Colorectal Cancer
Cancer Genomics & Proteomics, 2021
Background/Aim: Colorectal cancer is currently the third leading cause of cancer-related deaths and recently, alternative splicing has risen as its important regulator and potential treatment target. In the present study, we analyzed gene expression of the MBNL family of regulators of alternative splicing in various stages of colorectal cancer development, together with the MBNL-target splicing events in FOXP1 and EPB41L3 genes and tumor-related CD44 variants. Materials and Methods: Samples of tumor tissue and non-malignant mucosa from 108 patients were collected. After RNA isolation and reverse transcription, the relative gene expression of a selected gene panel was tested by quantitative real-time PCR, followed by statistical analysis. Results: MBNL expression was decreased in tumor tissue compared to non-tumor mucosa. In addition, lower expression was observed for the variants of FOXP1 and EPB41L3, while higher expression in tumor tissue was detected both for total CD44 and its cancer-related variants 3 and 6. Transcript levels of the MBNL genes were not found to be related to any of the studied clinicopathological characteristics. Multiple significant associations were identified in the target gene panel, including higher transcript levels of FOXP1 and CD44v3 in patients with distant metastases and connections between recurrence-free survival and altered levels of FOXP1 and CD44v3. Conclusion: Our results identified for the first-time deregulation of MBNL genes in colorectal cancer. Down-regulation of their transcripts in tumor tissue compared to matched non-tumor mucosa can lead to transition of alternative splicing patterns towards a less differentiated phenotype, which highlights the importance of alternative splicing regulation for tumor growth and propagation. Colorectal cancer (CRC) remains the third most commonly diagnosed malignancy in males and the second most commonly diagnosed cancer in females (1, 2). Globally, colorectal cancer is among the leading causes of cancer-related deaths (3, 4). Although the incidence of CRC has been steadily rising worldwide over the last few decades, especially in developing countries (3), the overall survival rate has increased as well with advances in targeted agents and cytotoxic chemotherapy (4, 5). Also, improvements in CRC screening result in disease detection at lower stages when it is easier to remove the tumor by surgery before metastatic spread occurs (6). In general, treatment choice is based on multiple factors, including clinical features (e.g. tumor location, stage at detection), demographic variables (e.g. sex, age at diagnosis, and familial risk), and characteristics of the tumor (e.g. microsatellite instability, somatic mutations) (7, 8). In addition to common prognostic factors and therapeutic targets, evidence accumulated during the past decades has revealed novel markers. In particular, the importance of alternative splicing dysregulation during colorectal cancer development has been observed, opening new aspects of specific modifications of splicing regulatory proteins and pathologic splicing events in CRC (9, 10). Alternative splicing (AS) is known as an important posttranscriptional process that enables formation of multiple 295 This article is freely accessible online.
Experimental and therapeutic medicine, 2012
Colorectal cancer (CRC) is one of the most frequent neoplasms and is responsible for the second highest mortality rate of all cancers in the more developed regions of the world. The molecular mechanisms of CRC are relatively well characterized and are correlated to the accumulation of genetic mutations and certain patterns of gene expression/over-expression. There are a number of possible molecular factors involved in CRC progression in the aforementioned pathways, which are as yet not well described. One of these factors appears to be the gene FJ 194940.1, previously termed P65. FJ 194940.1 consists of 6 exons and probably undergoes alternative splicing in malignant tissues. In this study, tissue samples from 102 patients with colon cancer were investigated to confirm alternative splicing and to correlate results obtained with clinicopathological parameters. A total of 18 splice variants, which arise from various combinations of 4 exons (II, III, IV and V) and exon-exon junctions b...
Role of Aberrant Alternative Splicing in Cancer
Jorjani Biomedicine Journal, 2021
Alternative splicing can alter genome sequence and as a consequence, many genes change to oncogenes. This event can also affect protein function and diversity. The growing number of study elucidate the pathological influence of impaired alternative splicing events on numerous disease including cancer. Here, we would like to highlight the significant role of alternative splicing in cancer biology and emphasize the necessity for conducting more research into target alternative splicing as a treatment for cancer.
Molecular & Cellular Oncology, 2014
In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing.
Journal of proteome research, 2018
We investigated new transcription and splicing factors associated with the metastatic phenotype in colorectal cancer. A concatenated tandem array of consensus transcription factor (TF)-response elements was used to pull down nuclear extracts in two different pairs of colorectal cancer cells, KM12SM/KM12C and SW620/480, genetically related but differing in metastatic ability. Proteins were analyzed by label-free LC-MS and quantified with MaxLFQ. We found 240 proteins showing a significant dysregulation in highly metastatic KM12SM cells relative to nonmetastatic KM12C cells and 257 proteins in metastatic SW620 versus SW480. In both cell lines there were similar alterations in genuine TFs and components of the splicing machinery like UPF1, TCF7L2/TCF-4, YBX1, or SRSF3. However, a significant number of alterations were cell-line specific. Functional silencing of MAFG, TFE3, TCF7L2/TCF-4, and SRSF3 in KM12 cells caused alterations in adhesion, survival, proliferation, migration, and live...
BMC Genomics, 2006
Background: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression.
Alternative Splicing as a Target for Cancer Treatment
International journal of molecular sciences, 2018
Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination of splicing sites, exonic or intronic sequences, mutually exclusive exons or retained introns could be selected during alternative splicing to generate different mature mRNAs that could in turn produce distinct protein products. Alternative splicing is the main source of protein diversity responsible for 90% of human gene expression, and it has recently become a hallmark for cancer with a full potential as a prognostic and therapeutic tool. Currently, more than 15,000 alternative splicing events have been associated to different aspects of cancer biology, including cell proliferation and invasion, apoptosis resistance and susceptibility to different chemotherapeutic drug...
Cells, 2019
Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC.