Abstract
Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.
Highlights
1234567890():,; Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer
We find the high expression of an exon 10inclusive form of SREK1 (SREK1L) in Hepatocellular carcinoma (HCC) tumor tissues (HCCT) that is associated with poor prognosis of the patients, and demonstrate that SREK1L promotes the oncogenesis of HCC cells in vitro and in vivo through its interactions with NMD components to regulate the expression of BLOC1S5-TXNDC5 (B-T)
The expression of SREK1L and SREK1S was determined by PCR using primer set 1 (Supplementary Fig. 1b), and the percentage-splice-in (PSI) was analyzed in each sample, which was significantly higher in HCCT than in matched normal tissues (HCC-MN) (Fig. 1a, b)
Summary
1234567890():,; Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. We report a functional impact of a Splicing Regulatory Glutamine/LysineRich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). Characterizing the functional impact of AS variants, their regulators, and the signaling pathways involved is critical for interpreting the effects of aberrant isoform expression leading to hepatocarcinogenesis and/ or metastasis, and for the rational design of therapeutic strategies. We find the high expression of an exon 10inclusive form of SREK1 (SREK1L) in HCC tumor tissues (HCCT) that is associated with poor prognosis of the patients, and demonstrate that SREK1L promotes the oncogenesis of HCC cells in vitro and in vivo through its interactions with NMD components to regulate the expression of BLOC1S5-TXNDC5 (B-T). SRSF10 is shown to be significantly upregulated in HCCT and further promote the oncogenesis of HCC cells by maintaining the inclusion of SREK1 exon 10
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