Author:
Zhou Yue,Chen Enjiang,Tang Yuexiao,Mao Jiayan,Shen Jian,Zheng Xiaoxiao,Xie Shangzhi,Zhang Shufen,Wu Ying,Liu Hao,Zhi Xiao,Ma Tao,Ni Haibin,Chen Jiabin,Chai Kequn,Chen Wei
Abstract
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.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
65 articles.
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