miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells
miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells
复制标题
miR-223过表达通过靶向FOXO3a抑制阿霉素诱导的自噬并逆转肝细胞癌细胞的化疗耐药性
DOI：
10.1038/s41419-019-2053-8
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发表时间：
2019-11-06
影响因子：
9
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Zhou, Yue;Chen, Enjiang;Chen, Wei
阿霉素通常用于肝细胞癌（HCC）的化疗，但在长期治疗过程中产生的获得性耐药性限制了其益处。自噬是一种保守的细胞自我保护和适应环境变化的分解代谢过程，被认为是克服阿霉素耐药性的潜在临床靶点。在这项研究中，miR-223在调节阿霉素诱导的自噬和敏感性中的潜在作用在四种转染的人HCC细胞系中进行了评估，并使用HCC的小鼠异种移植模型评估了体内相关性。我们发现定义明确的miR-223在阿霉素处理的HCC细胞中以低水平表达，并且miR-223过表达抑制阿霉素诱导的自噬，该自噬有助于化疗耐药性。氯喹阻断自噬流导致miR-223抑制剂不能抑制HCC细胞对阿霉素的敏感性。我们进一步确定FOXO 3a是miR-223的直接下游靶点，也是miR-223对HCC细胞中阿霉素诱导的自噬和化疗耐药性的调节作用的主要介质。最后，我们证实了agomiR-223在HCC异种移植模型中对阿霉素敏感性的增强。这些发现建立了一种新的基于miRNA的自噬干扰方法，以逆转未来针对人类HCC的化疗方案中的多柔比星耐药性。
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.