HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma.

Abstract

Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with β-catenin in the cytoplasm to reduce the nuclear translocation of β-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/β-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.

• Authors: Xian Lin, Shi Zuo, Rongcheng Luo, Yonghao Li, Guifang Yu, Yujiao Zou, Yan Zhou, Zhan Liu, Yiyi Liu, Yingying Hu, Yingying Xie, Weiyi Fang, Zhen Liu
• Journal: Theranostics (Theranostics) Vol. 9 Issue 25 Pg. 7583-7598 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 31695788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• CTNNB1 protein, human
• FOXO1 protein, human
• Forkhead Box Protein O1
• MicroRNAs
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• beta Catenin
• hepatitis B virus X protein

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Forkhead Box Protein O1 (metabolism)
• Gene Expression Regulation, Neoplastic (physiology)
• Hep G2 Cells
• Humans
• Liver Neoplasms (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• MicroRNAs (metabolism)
• Neoplasm Recurrence, Local (metabolism)
• Neoplastic Stem Cells (metabolism)
• Trans-Activators (metabolism)
• Viral Regulatory and Accessory Proteins (metabolism)
• Wnt Signaling Pathway (physiology)
• beta Catenin (metabolism)