HnRNP-F Regulates EMT in Bladder Cancer by Mediating the Stabilization of Snail mRNA Through Binding to Its 3'UTR

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Background: Heterogeneous nuclear ribonucleoprotein F (HnRNP-F) has previously been implicated in multiple cancers, suggesting its roles in tumorigenesis, but the potential oncogenic role and mechanism of hnRNP-F in bladder cancer (BC) remains incompletely understood. Methods: HnRNP-F was identified by proteomic methods. A correlation of hnRNP-F expression with the prognosis was analyzed in103 BC patients. Then, we applied in vitro and in vivo methods to reveal the behaviors of hnRNP-F in BC tumorigenesis. Furthermore, the interaction between hnRNP-F and Snail mRNA was examined by RNA immunopreciptiation (RIP), and Snail mRNA stability was measured after treatment with actinomycin D. Finally, the binding domain between hnRNP-F and Snail mRNA was tested through Snail mRNA truncations and mutants. Finding: HnRNP-F is significantly up-regulated in BC tissue, and its increased expression is associated with poor prognosis in BC patients. HnRNP-F was necessary for tumor growth, inducing Epithelial-mesenchymal transition (EMT) and metastasis in BC. The changes of Snail expression were positively consistent with hnRNP-F in both mRNA and protein levels when hnRNP-F was silenced or enhanced, suggesting that Snail is likely to be the downstream target of hnRNP-F that mediates its effects on enhancing invasion, metastasis and EMT in BC. Overexpression of hnRNP-F caused an increase in the stability of the Snail mRNA was enhanced. Our RNA chip analysis revealed that hnRNP-F could combine with the Snail mRNA, and we further demonstrated that hnRNP-F could directly bind to the 3'untranslated region (3'UTR) of Snail mRNA to enhance its stability. Interpretation: Our findings suggest that hnRNP-F mediates the stabilization of Snail mRNA via binding to its 3'UTR, subsequently regulating EMT. Funding Statement: This study was supported by Natural Science Foundation Committee of China (NSFC 81802941) (F.L.), and the Natural Science Foundation of Guangdong Province of China (2018A0303130287) (F.L.). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All patients were given written informed consent and all procedures were approved by bioethics committee of the authors' hospital.