microRNA-93-5p promotes hepatocellular carcinoma progression via a microRNA-93-5p/MAP3K2/c-Jun positive feedback circuit.

Abstract

Cumulative evidence suggests that microRNAs (miRNAs) promote gene expression in cancers. However, the pathophysiologic relevance of miRNA-mediated RNA activation in hepatocellular carcinoma (HCC) remains to be established. Our previous miRNA expression profiling in seven-paired HCC specimens revealed miR-93-5p as an HCC-related miRNA. In this study, miR-93-5p expression was assessed in HCC tissues and cell lines by quantitative real-time PCR and fluorescence in situ hybridization. The correlation of miR-93-5p expression with survival and clinicopathological features of HCC was determined by statistical analysis. The function and potential mechanism of miR-93-5p in HCC were further investigated by a series of gain- or loss-of-function experiments in vitro and in vivo. We identified that miR-93-5p, overexpressed in HCC specimens and cell lines, leads to poor outcomes in HCC cases and promotes proliferation, migration, and invasion in HCC cell lines. Mechanistically, rather than decreasing target mRNA levels as expected, miR-93-5p binds to the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to directly upregulate its expression and downstream p38 and c-Jun N-terminal kinase (JNK) pathway, thereby leading to cell cycle progression in HCC. Notably, we also demonstrated that c-Jun, a downstream effector of the JNK pathway, enhances miR-93-5p transcription by targeting its promoter region. Besides, downregulation of miR-93-5p significantly retarded tumor growth, while overexpression of miR-93-5p accelerated tumor growth in the HCC xenograft mouse model. Altogether, we revealed a miR-93-5p/MAP3K2/c-Jun positive feedback loop to promote HCC progression in vivo and in vitro, representing an RNA-activating role of miR-93-5p in HCC development.

• Authors: Xuan Shi, Tao-Tao Liu, Xiang-Nan Yu, Asha Balakrishnan, Hai-Rong Zhu, Hong-Ying Guo, Guang-Cong Zhang, Enkhnaran Bilegsaikhan, Jia-Lei Sun, Guang-Qi Song, Shu-Qiang Weng, Ling Dong, Michael Ott, Ji-Min Zhu, Xi-Zhong Shen
• Journal: Oncogene (Oncogene) Vol. 39 Issue 35 Pg. 5768-5781 (08 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32719439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• MIRN93 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins c-jun
• MAP Kinase Kinase Kinase 2
• MAP3K2 protein, human

Topics

• 3' Untranslated Regions
• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Hep G2 Cells
• Heterografts
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• MAP Kinase Kinase Kinase 2 (biosynthesis, genetics, metabolism)
• Male
• Mice
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Phosphorylation
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Transfection
• Up-Regulation