Loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CDC28 protein kinase regulatory subunit 1B.

Minghua Hu,Xiaoshan Fang,Hongping Xia,Xiaoming Wang,Jinguo Wang,Mingwei Wang,Xiaobing Chen,Huihong Lu,Chenyang Ma

doi:10.18632/oncotarget.9728

Abstract

Hepatocellular carcinoma (HCC) is the leading cause of cancer related death worldwide. The number of deaths is proportional to the global incidence, which highlights the aggressive tumor biology and lack of effective therapies. Dysregulation of microRNAs has been implicated in carcinogenesis and progression of liver cancer. Here, we identified that miR-1258 was significantly downregulated in HCC and associated with poor patients' survival. Overexpression of miR-1258 significantly inhibits liver cancer cell growth, proliferation and tumorigenicity through increasing cell cycle arrest in G0/G1 phase and promotes cell apoptosis. Interestingly, stable overexpression of miR-1258 suppresses cell migration, stemness and increases sensitivity of HCC cells to chemotherapy drug like doxorubicin. The CDC28 protein kinase regulatory subunit 1B (CKS1B) was identified as a functional downstream target of miR-1258. Re-expression of CKS1B overcomes miR-1258 induced apoptosis and increases stemness of HCC cells, suggesting that loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CKS1B. Therefore, loss of miR-1258 may be a potential diagnostic and prognostic biomarker and blocking miR-1258-CKS1B axis is a potential therapeutic strategy in HCC.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer (70%–90%) and is seen more often in men than in women
We found that miR-1258 was significantly downregulated in HCC and associated with poor patients’ survival
The results showed that the expression of miR-1258 was significantly downregulated in HCC tissues compared to adjacent normal samples (Figure 1C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer (70%–90%) and is seen more often in men than in women. It is the second leading cause of cancer death among men in developing countries and the sixth leading cause of cancer death among men in developed countries. The current management of HCC patients includes surgical resection, liver transplantation, radiofrequency ablation, transcatheter arterial chemoembolization (TACE) or sorafenib. Most patients are still diagnosed at advanced disease stages, and in this setting, sorafenib is currently the only FDA approved targeted therapy drug to improve overall survival. The study of novel factors contributing to carcinogenesis and progression of liver cancer needs to be investigated

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Conclusion