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, 6,019 (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.

Characterizing isoform switching events in esophageal adenocarcinoma

“…Two reports characterizing isoform switching events in ESCC identified numerous unique isoforms with only MINDY1 as a gene in common with our isoform switch analysis, supporting divergent molecular changes based on esophageal cancer subtype. 36,49 MINDY-1, also known as FAM63A, is a newly identified deubiquitinating protein that preferentially removes K48-linked ubiquitin molecules. 50 In BE and EAC, MINDY1 was identified in a set of 90 genes significantly predicting disease progression by distinguishing EAC progressors from patients with non-dysplastic BE.…”

“…In ESCC, reported isoform switching events were dominated by cell regulation of cell motility, cell-to-cell junction organization, regulation of cell migration, and adhesion-linked GO processes. 49 Select isoform-switched genes in our BE progression dataset hold some similar functions. For example, isoform switching of TPM4 was originally observed in breast cancer with loss of TPM4.1 associated with increased migration, disruption of cell-cell adhesions, and cancer invasiveness.…”

SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

“…SF3B4 is a splicing factor whose mutation is a major cause of Nager Syndrome (Liu et al, 2018). SF3B4 has been reported as an oncogenic driver in several tumor types, including HCC and esophageal cancer, while in pancreatic cancer, it acts as a tumor-suppressor protein (Ding et al, 2021;Iguchi et al, 2016;Kidogami et al, 2020;Lee et al, 2020;Liu et al, 2018;Lv et al, 2020;Wang et al, 2020;Xu et al, 2015;Zhou et al, 2017). In this study, using a siRNA-based knockdown strategy with cell growth and cell cycle analysis, we demonstrated for the first time that SF3B4 exhibits oncogenic properties in A549 NSCLC cells.…”

“…Moreover, the miRNA-133b and Ser/Arg (SR)-rich splicing factor (SRSF) 3 are known to regulate SF3B4 levels (Lee et al, 2020;Liu et al, 2018). Clinicopathological and transcriptome data also demonstrated an oncogenic role of SF3B4 in esophageal squamous cell carcinoma and adrenocortical carcinoma (Ding et al, 2021;Kidogami et al, 2020;Lv et al, 2020). In contrast, SF3B4 expression is lower in pancreatic cancer than in adjacent normal tissues.…”

Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations

“…The mutated gene SF3B4 in Family 2, encodes one of the components of the splicing factor 3b (SF3b) complex 32. The loss or gain of function caused by SF3b4 mutations is frequently associated with aberrant cell development and plays a role in the pathogenesis of various cancers including hepatocellular carcinoma, ovarian cancer and oesophagus squamous cell carcinoma 33–36. Whether SF3B4 plays a role in SSC self-renewal, leading to selfish spermatogonial selection, requires further investigation.…”