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RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing.

ABSTRACT: The prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

SUBMITTER: Yan Q

PROVIDER: S-EPMC8049873 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAberrant alternative splicing events play critical roles in carcinogenesis and progression of many cancers, while sparse studies regarding to alternative splicing are available for clear cell renal cell carcinoma (ccRCC). We identified that alternative splicing of coiled-coil domain containing 50 (CCDC50) was dysregulated in ccRCC, whereas the clinical significance of this splicing event and its splicing regulation mechanisms were still elusive.MethodsBioinformatic algorithm was utilized to identify significant exon skipping events in ccRCC via exon sequencing data from The Cancer Genome Atlas. Semi-quantitative real-time polymerase chain reaction and western blot were used to validate the aberrant expression of different transcripts in renal cancer tissues, cell lines and corresponding noncancerous controls. Short hairpin RNA targeting CCDC50 and overexpressing plasmids for each transcript were introduced into ccRCC cell lines, followed by a series of in vitro and in vivo functional experiments. Moreover, a panel of splicing factors were identified and their roles on splicing regulation of CCDC50 precursor mRNA (pre-mRNA) were studied. Furthermore, RNAseq data were analyzed to elucidate downstream molecules of CCDC50. Two-way analysis of variance and unpaired Student t test were used in statistical analysis.ResultsPre-mRNA of CCDC50 generated two transcripts, full-length transcript (CCDC50-FL) and truncated transcript (CCDC50-S) with exon 6 skipped. CCDC50-S was overexpressed in ccRCC tissues and cell lines compared to noncancerous counterparts, but CCDC50-FL was only detected in noncancerous tissues and normal renal epithelial cells. Higher percent spliced-in index was associated with better survival in ccRCC patients. In vitro and in vivo functional experiments indicated that CCDC50-S transcript promoted the proliferation, migration, invasion and tumorigenesis of ccRCC, while CCDC50-FL exerted opposite tumor suppressive functions. Besides, we identified that heterogeneous nuclear ribonucleoprotein A1 (HnRNP A1) could promote the skipping of exon 6, which resulted in higher portion of CCDC50-S and oncogenic transformation. Moreover, zinc finger protein 395 (ZNF395) was identified as a downstream protein of CCDC50-S, and the interaction initiated oncogenic pathways which were involved in ccRCC progression.ConclusionsAberrant alternative splicing of CCDC50 is regulated by HnRNP A1 in ccRCC. This splicing event contributes to cancer progression through the downstream pathway involving ZNF395.

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RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing.

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