The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma

Author:

Chang CunjieORCID,Rajasekaran Muthukumar,Qiao Yiting,Dong Heng,Wang YuORCID,Xia HongpingORCID,Deivasigamani Amudha,Wu Minjie,Sekar Karthik,Gao Hengjun,Sun Mengqing,Niu Yuqin,Li Qian,Tao Lin,Yan Zhen,Wang Menglan,Chen Shasha,Zhao Shujuan,Chen Dajing,Li Lina,Yang Fan,Gao Haojin,Chen Baodong,Su Ling,Xu LiangORCID,Chen YeORCID,Seshachalam Veerabrahma Pratap,Chen Gongxing,Gunaratne Jayantha,Hong WanjinORCID,Shi Junping,Chen Gongying,Grierson David S.,Chabot BenoitORCID,Xie TianORCID,Hui Kam ManORCID,Chen JianxiangORCID

Abstract

AbstractDeregulation 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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