Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Abstract

KEYWORDS 2Alternative splicing (AS), colorectal cancer (CRC), metastasis, RNA-seq, TCGA 3 Abstract Alternative splicing is an important mechanism of regulating eukaryotic gene expression.Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

Unraveling Candidate Biomarkers and Involved Biomedical Phenomena in Colorectal Cancer by Systematic Proteomics Analysis and Experimental procedures

“…It is also worth mentioning that AS events could be considered potential therapeutic targets for CRC. In this regard, the increased expression of COL6A3 as a survival element in CRC has been recently reported [25]. Remarkably, our result in network analysis revealed SF3B3 as the highest-scoring central protein known as the main splicing element in the mRNA splicing pathway, which has not yet been investigated in CRC advancement.…”

Splicing factor arginine/serine‐rich 8 promotes multiple myeloma malignancy and bone lesion through alternative splicing of CACYBP and exosome‐based cellular communication

“…We validated the existence of two CACYBP splicing isoforms, CACYBP isoform1 (NM_014412.3) and CACYBP isoform2 (NM_001007214.1). The distinct protein isoforms yielded by the identical gene through alternative splicing may possess related, different or even opposite functions 54 . The conserved domains in both isoforms of CACYBP guarantee the function of promoting ubiquitination.…”

Hexokinase domain-containing protein-1 in metabolic diseases and beyond

“…This finding suggests a regulatory role of specific miRNAs in curbing HKDC1 expression. Lian et al [47] examined alternative splicing events in HKDC1 in colorectal cancer (CRC), a leading cause of mortality in developed countries [48]. Through RNA-seq analysis of paired CRC and normal tissues, significant splicing differences were found in nine genes in CRC and confirmed by The Cancer Genome Atlas data amongst CRC tumors and normal controls.…”

“…Cell lines: SW480, human colon adenocarcinoma cell line, grade 3-4; SW620, metastatic human colon adenocarcinoma cell line obtained from lymph node; A549, non-small cell lung carcinoma cell line derived from adenocarcinomic lung tissue; H1299, metastatic non-small cell lung carcinoma cell line obtained from lymph node; MCF7, human breast cancer cell line. See also [43,45,47,[50][51][52][53].…”