Dataset Information

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

ABSTRACT: The deregulation of alternative splicing (AS) has recently been implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms on regulatory network of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) on sustaining the oncogenic signal.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Suat Peng Neo

LAB HEAD: Jayantha GUNARATNE

PROVIDER: PXD030800 | Pride | 2022-05-20

REPOSITORIES: Pride

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Publications

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

Chang Cunjie C Rajasekaran Muthukumar M Qiao Yiting Y Dong Heng H Wang Yu Y Xia Hongping H Deivasigamani Amudha A Wu Minjie M Sekar Karthik K Gao Hengjun H Sun Mengqing M Niu Yuqin Y Li Qian Q Tao Lin L Yan Zhen Z Wang Menglan M Chen Shasha S Zhao Shujuan S Chen Dajing D Li Lina L Yang Fan F Gao Haojin H Chen Baodong B Su Ling L Xu Liang L Chen Ye Y Seshachalam Veerabrahma Pratap VP Chen Gongxing G Gunaratne Jayantha J Hong Wanjin W Shi Junping J Chen Gongying G Grierson David S DS Chabot Benoit B Xie Tian T Hui Kam Man KM Chen Jianxiang J

Nature communications 20220316 1

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 (SREK1<sup>L</sup>). SREK1< ...[more]

PMID: 35296659

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Project description:MSI (Microsatellite Instability) colorectal cancer (CRC) show improved survival, are less prone to metastasis and show poor response to chemotherapy (compared to MSS tumors). The underlying reasons for these characteristics are still not understood and no specific therapeutic approach for MSI colon tumours (15% of CRC overall) has yet been developed. The MSI process is oncogenic when it affects DNA repeat sequences that have a functional role, e.g. Small Coding Repeats (SCR). MSI also frequently affects Long Non-Coding Repeats (LNCR) in tumour DNA. In contrast to SCR, only a few LNCR are endowed with biological activity. Consequently, this area has received very little attention. Our group recently identified HSP110 mutant chaperone protein in MSI CRC that was generated by somatic deletion of a LNCR. Of interest, HSP110 mutant (due to exon skipping) have anti-oncogenic properties and the survival of MSI CRC patients receiving chemotherapy is positively associated with HSP110 mutations in tumour DNA. The aim of the current project is to identify additional clinically relevant MSI-associated splicing aberrations due to mutations in LNCR located in splice acceptor sites. The four main steps are as follows: 1. To identify exon/intron sites affected by aberrant splicing events due to MSI in CRC . All RNASeq data will be exploited to identify recurrent splicing aberrations (mostly exon skipping) that occur specifically in MSI colon tumours; 2. To investigate for possible functional links between MSI and any detected aberrant splicing events . All specific aberrant splicing events detected by RNAseq in MSI CRC samples will be first confirmed (quantitative RT-PCR) in order to eliminate false positive cases. For validated exon candidates, the allelic profiles of adjacent intronic LNCR will be analysed (PCR and fluorescence genotyping) in CRC cell lines and primary tumours (MSI and MSS), as well as in matching normal mucosa samples in order to assess their polymorphic status; 3. To identify splicing events and LNCR mutations with clinical relevance in MSI CRC patients . All LNCR with a confirmed role in gene splicing in MSI CRC will be analysed. The clinical relevance of candidate genes will be assessed using multivariate survival regression models for Relapse- Free Survival, with interaction terms (response to chemotherapy); 4. To initiate functional studies on a limited number of clinically relevant, cancer-related genes whose splicing is perturbed in MSI cancer cells, and to develop biological tools to simplify screening in future clinical assays Similar to HSP110, we will focus on 4 or 5 mutant proteins that are promising drug therapeutic targets. Functional assays will be developed to further elucidate their role in the pathophysiology of MSI tumours. We also aim to develop biological tools for these candidate genes, such as the detection of wild-type or mutant proteins by immunohistochemistry.

Dataset Information

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

Publications

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

Similar Datasets

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