MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

Weihua Ren,Yawei Li,Xingpeng Zhao,Shuangting Wu,Tan Liu,Yabin Wu

doi:10.1038/s41419-019-1530-4

Weihua Ren, Yawei Li + Show 4 more

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https://doi.org/10.1038/s41419-019-1530-4

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microRNAs (miRNAs) play essential roles in progression of hepatocellular carcinoma (HCC). However, the roles of miR-196a and miR-196b as well as mechanism in HCC progression remain poorly understood. The expressions of miR-196a, miR-196b and suppressor of cytokine signaling 2 (SOCS2) were measured in HCC tissues and cells by quantitative real-time polymerase chain reaction or immunohistochemistry. HCC progression was investigated by cell proliferation, glycolysis, cycle, clones, apoptosis, and necrosis. The interaction between SOCS2 and miR-196a or miR-196b was explored by luciferase activity and RNA immunoprecipitation analyses. The expressions of proteins in Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway were measured by western blot. A xenograft model was established to investigate the roles of miR-196a or miR-196b in vivo. We found that miR-196a and miR-196b were highly expressed in HCC tissues and cells. High expression of miR-196a or miR-196b was correlated with tumor size, tumor-node-metastasis stage, lymph node metastasis, albumin–bilirubin grade and poor 5-year survival. Knockdown of miR-196a or miR-196b suppressed cell proliferation, glycolysis, cell cycle process, colony formation but induced apoptosis or necrosis in HCC cells. SOCS2 was targeted by miR-196a and miR-196b and its interference ablated abrogation of miR-196a or miR-196b-mediated inhibitory effect on HCC progression. SOCS2 was negatively associated with activation of the JAK/STAT pathway. Besides, knockdown of miR-196a or miR-196b limited xenograft tumor growth by blocking the JAK/STAT pathway. We concluded that downregulation of miR-196a or miR-196b inhibited HCC progression through regulating the JAK/STAT pathway via targeting SOCS2, providing novel targets for prognosis and therapeutics of HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer death with rising incidence worldwide[1]
The morphology investigation of HCC and peri-tumor tissues using hematoxylin and eosin (H&E) staining displayed that stained HCC tissues showed typical HCC morphology with many formed balloon-like lesions and the peri-tumor tissues exhibited normal liver cell morphology (Fig. S1)
Bioinformatics analysis suggested that miR-196a and miR-196b were highly expressed in HCC tissues compared with that in normal tissues by YM500v3 (Fig. S2A and S2B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer death with rising incidence worldwide[1]. We measured the expression of miR-196a and miR-196b and explored their roles as well as underlying mechanism in HCC progression. Cell apoptosis and proliferation in tumor tissues were measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining with in situ cell death detection kit (Roche, Mannheim, Germany) or Ki67 immunohistochemistry with anti-Ki67 antibody (ab16667, 1:1000 dilution, Abcam) following the manufacturer’s instructions as previous study[20].

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