J Cancer 2021; 12(1):281-291. doi:10.7150/jca.50490

Research Paper

HnRNP-F promotes the proliferation of bladder cancer cells mediated by PI3K/AKT/FOXO1

Fei Li1*, Weiwei Xie1*, Yunze Fang1, Kunfeng Xie1, Wendong Liu1, Lina Hou2✉*, Wanlong Tan1✉*

1. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R.China.
2. Department of Healthy Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China.
*These authors contributed equally to this manuscript.

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Li F, Xie W, Fang Y, Xie K, Liu W, Hou L, Tan W. HnRNP-F promotes the proliferation of bladder cancer cells mediated by PI3K/AKT/FOXO1. J Cancer 2021; 12(1):281-291. doi:10.7150/jca.50490. Available from https://www.jcancer.org/v12p0281.htm

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Our previous study showed that heterogeneous nuclear ribonucleoprotein F (hnRNP-F) could induce epithelial-mesenchymal transition and metastasis in bladder cancer (BC), however, the role and mechanism of hnRNP-F in mediating the proliferative ability of BC cells remain unclear. HnRNP-F promoted the proliferation of BC cells by using BC cell lines and cell counting kit-8 (CCK8), colony formation and flow cytometry assays in vitro. Furthermore, the association of hnRNP-F with the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signalling pathway was confirmed by western blotting after bioinformatic analysis. HnRNP-F expression was significantly decreased by treatment with the PI3K/AKT signalling pathway inhibitor LY294002, whereas hnRNP-F knockdown did not significantly affect PI3K or AKT expression, suggesting that hnRNP-F is likely a downstream target of the PI3K/AKT pathway. Forkhead box O1 (FOXO1) is a molecule downstream of PI3K/AKT and can be inhibited by phosphorylation. In addition, chromatin immunoprecipitation (ChIP) and luciferase reporter assays indicated that FOXO1 expression was negatively correlated with hnRNP-F expression as FOXO1 was found to bind to the promoter region of hnRNP-F mRNA and inhibit its transcription. To sum up, our findings suggest that hnRNP-F expression is regulated by the PI3K/AKT-mediated phosphorylation of FOXO1, with phosphorylation inhibiting FOXO1, which subsequently allows hnRNP-F to promote proliferation. This finding is a novel discovery in BC and could help reveal the mechanism of BC progression.

Keywords: Heterogeneous nuclear ribonucleoprotein F, Phosphoinositide 3‑kinase/protein kinase B signalling pathway, Bladder cancer, Forkhead box O1, Proliferation