MiR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells

Yue Zhou,Jiabin Chen,Ying Wu,Haibin Ni,Kequn Chai,Tao Ma,Hao Liu,Enjiang Chen,Shufen Zhang,Xiaoxiao Zheng,Jiayan Mao,Xiao Zhi,Yuexiao Tang,Jian Shen,Wei Chen,Shangzhi Xie

doi:10.1038/s41419-019-2053-8

Abstract

Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancies worldwide[1]
MiR-223 expression in doxorubicintreated hepatocellular carcinoma (HCC) cells was significantly decreased compared to untreated control (Fig. 1c)
Combining autophagytargeted agents with the traditional doxorubicin is regarded as a promising strategy to improve drug response8–10. miR-223 regulates many important cellular processes including multidrug resistance in HCC, and recent research indicates that miR-223 suppresses excessive autophagy[18,19,20,21,22,23,24]

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancies worldwide[1]. Doxorubicin treatment induces autophagy which contributes to the Official journal of the Cell Death Differentiation Association. Zhou et al Cell Death and Disease (2019)10:843 development of chemoresistance, and inhibition of autophagy effectively overcomes or reverses doxorubicin resistance in a variety of cancers[8,9,10]. Increasing evidence demonstrates that several miRNAs are implicated in doxorubicin resistance and are promising targets for combined treatment of HCC15–17. MiR-223, a commonly repressed miRNA in HCC cells, has been confirmed to be involved in many important physiological and pathological processes including proliferation, metastasis, and stemness maintenance in HCC, while miR-223 targeted therapy has good prospect for clinical application[18,19,20,21]. Whether miR-223 can modulate doxorubicin-induced autophagy in HCC cells remains unclear

Methods

Results

Conclusion