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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [Apc mutant and Apc Srsf1 double mutant]

ABSTRACT: mRNAseq of Apc mutant and Apc Srsf1 double mutant mouse small intestine.

ORGANISM(S): Mus musculus

PROVIDER: GSE199600 | GEO | 2022/03/31

REPOSITORIES: GEO

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [wild-type and Apc mutant]

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [Apc mutant and Apc Srsf1 double mutant]

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Project description:Adenomatous polyposis coli (APC) is an important tumor suppressor and most directly related to the regulation of WNT/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). However, obvious prognostic differences are observed in CRC patients with APC mutations. Although previous genomics has investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. By using combined proteome and phosphoproteome, we classified the APC-mutant colon cancer patients and revealed the genomic, proteomic and phosphoproteomic heterogeneity in APC-mutant tumors. Of importance, we identified RAI14 as a key prognostic determinant for APC-mutant colon cancer patients, but not for APC-wildtype colon cancer patients. The heterogeneity and prognostic biomarkers in APC-mutant tumors were further confirmed in Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that knockdown of RAI14 in cell lines led to reduced cell migration and changes in some epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 was able to remodel the phosphoproteome associated with cell adhesion, which might promote F-action degradation and alter the expression of certain EMT markers. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies the prognostic determinants for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.

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