RBM10 C761Y Mutation Induced Oncogenic ASPM Isoforms and Regulated β-catenin Signaling in Cholangiocarcinoma

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2024 Apr 4

PMID 38576051

Authors

Jiang Chang

Yaodong Zhang

Tao Zhou

Qian Qiao

Jijun Shan

Yananlan Chen

Wangjie Jiang

Yirui Wang

Shuochen Liu

Yuming Wang

Yue Yu

Changxian Li

Xiangcheng Li

Affiliations

Soon will be listed here.

Abstract

Background: Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear.

Methods: RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events.

Results: RBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the CH-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced β-catenin signaling, which promoted CCA progression.

Conclusions: Our results showed that RBM10-modulated ASPM203 promoted CCA progression in a Wnt/β-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

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