Alterations of RNA splicing patterns in esophagus squamous cell carcinoma

Abstract

Alternative splicing (AS) is an important biological process for regulating the expression of various isoforms from a single gene and thus to promote proteome diversity. In this study, RNA-seq data from 15 pairs of matched esophageal squamous cell carcinoma (ESCC) and normal tissue samples as well as two cell lines were analyzed. AS events with significant differences were identified between ESCC and matched normal tissues, which were re-annotated to find protein coding genes or non-coding RNAs. A total of 45,439 AS events were found. Of these, 6019 (13.25%) significant differentially AS events were identified. Exon skipping (SE) events occupied the largest proportion of abnormal splicing events. Fifteen differential splicing events with the same trends of ΔΨ values in ESCC tissues, as well in the two cell lines were found. Four pathways and 20 biological processes related to pro-metastasis cell junction and migration were significantly enriched for the differentially spliced genes. The upregulated splicing factor SF3B4, which regulates 92 gene splicing events, could be a potential prognostic factor of ESCC. Differentially spliced genes, including HNRNPC, VCL, ZNF207, KIAA1217, TPM1 and CALD1 are shown with a sashimi plot. These results suggest that cell junction- and migration-related biological processes are influenced by AS abnormalities, and aberrant splicing events can be affected by splicing factor expression changes. The involved splicing factor SF3B4 was found to be a survival-related gene in ESCC and is presumed to regulate AS in multiple cancers. In summary, we identified significant differentially expressed AS events which may be related to the development of ESCC.

Exploiting the Molecular Basis of Oesophageal Cancer for Targeted Therapies and Biomarkers for Drug Response: Guiding Clinical Decision-Making

“…Intron retention (RI) events and finally events involving mutually exclusive exons (MEE). ( B ) Percentages of differentially spliced AS events between OSCC clinical samples and matched normal samples with fraction of each type of splicing event [ 93 ].…”

Prognostic Alternative Splicing Signatures in Esophageal Carcinoma

“…When comparing this to esophageal cancer samples, changes in the splicing pattern of 13.25% of these alternately spliced genes were detected. 19 The authors then performed a similar analysis on an esophageal cancer cell line, comparing it to a normal esophageal cell line, 32,891 splicing events were identified. Of these splicing events, 2.8% showed changes in their splicing profile.…”

“… Levels of long transcript are lower in cancer while levels of short form are higher CRC Alternative 5ʹ splice site event downregulating expression of long form. [ 19 ] CD44 Hyaluronon cell surface receptor CD44v6 (include exon 6. Gastric cancer [ 21 , 22 ] Cyclin D1 Promotes proliferation Exon 4 exclusion/Cyclin D1b Various Cyclin D1b levels increased [ 36 ] FIR Pre-mRNA splicing, apoptosis, and transcription regulation Expression of isoforms lacking exon 2 is increased Various FIRΔexon2 assists proliferation [ 35 ] GFG GFG RNA inhibits the expression of FGF-2 and inhibits proliferation Splice variant b is upregulated ESCC Splice variant b is upregulated [ 31 ] GHRHR Receptor for growth hormone Splice variant 1 (SV1) ESCC Splice variant 1 (SV1) [ 34 ] KIAA1217 Development Intron retention intron retention in these genes are repressed by SF3B4 NSCLC RI event for KIAA1217 [ 19 , 29 ] LCN2, NGAL Inhibits proteolytic enzymes Multiple splicing isoforms ESCC Expression of NGAL-2 and NGAL-3 increased in ESCC [ 24 ...…”

“… ESCC MUC1/C, D, and Z are expressed at higher levels as ESCC develops and progresses [ 30 , 82 ] PHF6 Transcriptional regulation Intron retention in these genes is repressed by SF3B4 ESCC Splice variants overexpressed in ESCC [ 19 , 33 ] SF3B4 Splicing factor Overexpression results in mis-splicing of tumor suppressor-genes. HCC Up-regulated in ESCC May play a role in the lymphatic progression [ 19 , 25 , 26 ] SRSF5 Splicing factor Controls the splicing of many isoforms on this list Various Intron retention in these genes are repressed by SF3B4 [ 19 , 32 ] TCF4 WNT signaling Exon 4 inclusion, Exon 13–16 exclusion or inclusion Various 11 if 16 isoforms have been isolated from ESCC [ 8 ] TPM1 Binding actin filaments Exon 6 of TPM1 has two types, TPM1-6A and TPM1-6B Bladder cancer and prostate cancer MXE event in TPM1s [ 19 ] VCL F-actin-binding cytoskeletal protein Inclusion of exon 19 CRC Increased isoform expression [ 19 , 27 ] …”

“…Of these splicing events, 2.8% showed changes in their splicing profile. 19 Another study examining the difference between esophageal cancer tissue and normal esophageal tissue from 79 patients identified 2326 AS events in 1738 genes and the alternate splicing in 1360 genes were determined to be significantly associated with overall survival of esophageal cancer patients. 20 Most of the oncogenic splicing events in ESCC seem to be related to the increased expression of isoforms related to increased proliferation, altered cell junction, and increased cell migration.…”