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Next Generation Sequencing Facilitates Quantitative Analysis of CD46-KO/control vector, CD46-KO/CD46-CYT1 and CD46-KO/CD46-CYT2 EJ-1 cells’ Transcriptomes

ABSTRACT: CD46 is well known to be involved in diverse biological processes. Although several splice variants of CD46 have been identified, little is known about the contribution of alternative splicing to its tumorigenic functions. Here we found that exclusion of CD46 exon13 is significantly increased in bladder cancer samples. In bladder cancer cell lines, enforced expression of CD46-CYT2 (exon13-skipping isoform) induced cell growth and migration, and promoted tumorigenicity in a xenograft model. While enforced expression of CD46-CYT1 (exon13-containing isoform) attenuated tumorigenicity, representing an inverse phenotype of CD46-CYT2. We also used RNA sequencing to identify changes in gene expression after CD46-CYT1 or CD46-CYT2 overexpression and found KRT19 is a key CD46-CYT2 target gene. Furthermore, we applied interaction proteomics to identify exhaustively the complexes containing CYT1 or CYT2 domain in EJ-1 cells. 320 proteins were identified that interact with CYT1 or/and CYT2 domain, including some well-known CYT1 partners and most of them are new interactors. The new CYT2 partners’ translation machinery, RPL17 and EIF5A, were confirmed by coimmunoprecipitation experiments. We demonstrated that CD46-CYT2 enhances mRNA translation perhaps through an interaction with the translation machinery. Strikingly, the splicing factor SRSF1 is upregulated in bladder cancer and stimulates exclusion of exon13. Importantly, SRSF1 is highly correlated with CD46 exon13 exclusion in clinical bladder cancer samples. Taken together, our findings contribute to understanding the role of CD46 in bladder cancer development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117135 | GEO | 2019/12/31

REPOSITORIES: GEO

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Next Generation Sequencing Facilitates Quantitative Analysis of CD46-KO/control vector, CD46-KO/CD46-CYT1 and CD46-KO/CD46-CYT2 EJ-1 cells’ Transcriptomes

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