MiR-122 Reverses the Doxorubicin-Resistance in Hepatocellular Carcinoma Cells through Regulating the Tumor Metabolism.

Chenwei Pan,Lingxiang Jin,Zhenzhen Pan,Yongping Chen,Xiaodong Wang,Yi Zheng,Jie Li,Keqing Shi,Yu-Jia Chang

doi:10.1371/journal.pone.0152090

Abstract

Doxorubicin (DOX) is one of the most commonly used anticancer drugs in the treatment of hepatoma. However, acquired drug resistance is one of the major challenges for the chemotherapy. In this study, a down-regulation of miR-122 was observed in doxorubicin-resistant Huh7 (Huh7/R) cells compared with its parental Huh7 cells, suggesting miR-122 is associated with the chemoresistance. Meanwhile, luciferase reporter assay proved that the PKM2 is the target of miR-122, and we reported that the glucose metabolism is significantly up-regulated in Huh7/R cells. Importantly, overexpression of miR-122 in Huh7/R cells reversed the doxorubicin-resistance through the inhibition of PKM2, inducing the apoptosis in doxorubicin-resistant cancer cells. Thus, this study revealed that the dysregulated glucose metabolism contributes to doxorubicin resistance, and the inhibition of glycolysis induced by miR-122 might be a promising therapeutic strategy to overcome doxorubicin resistance in hepatocellular carcinoma.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which is the third leading cause of cancer-related deaths [1]
We found that the expression of miR-122 was significantly down-regulated in HCC cell lines (Huh7, Hep3B, HepG2 and PLC) compared with the L-O2 cell line which is the normal hepatocytes (Fig 1A), suggesting miR-122 function as a tumor suppressor in HCC
All these results suggest that miR-122 is a tumor suppressor, and associated with doxorubicin resistance in HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which is the third leading cause of cancer-related deaths [1]. Surgery and liver transplants have high rate of cure for patients with early stage HCC, many patients are diagnosed when the disease has reached a stage beyond curative surgery [2]. In these cases, systemic chemotherapy is considered as an alternative option. Systemic chemotherapy is usually ineffective because of the resistance of cancer cells to chemotherapeutic agents, resulting in the high mortality from HCC [3]. Combined treatment with some sensitizing agents is desirable to increase the anti-tumor effect and overcome the DOX-resistance

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Results

Conclusion