Abstract
Abstract Background: The occurrence of invasion and metastasis is the major cause of mortality in melanoma. Recent studies suggest that dysregulated miRNAs play critical roles in this procedure, but the underlying mechanism remains elusive. Here, we show that down-regulated miR-23a can promote invasion-metastasis cascade through autophagy in melanoma.Methods: The role of miR-23a in prognosis was assessed in a cohort of melanoma patients (n = 192) with Kaplan-Meier analysis. The effects of miR-23a overexpression were investigated using assays of invasion, migration and in a xenograft model (n = 10 mice per group). Autophagy-related target of miR-23a was confirmed by bioinformatics analysis, luciferase assays and immunoblotting. Molecular studies were performed to determine the downstream cellular and molecular mechanisms. All statistical tests were two-sided.Results: Serum miR-23a level was significantly down-regulated in melanoma patients (P< .001) and was highly correlated with poor clinical outcomes (P = .027, log-rank test). In addition, miR-23a level was remarkably decreased in metastatic melanoma tissues and cell lines (P<.05, P<.01). Moreover, miR-23a overexpression prevented the invasion and migration in vitro and lung and liver metastasis in vivo (both P< .05), by targeting ATG12 and inhibiting autophagy. Mechanically, miR-23a-ATG12 axis attenuated invasion and migration through autophagy-mediated AMPK-RhoA pathway. Finally, the down-regulation of miR-23a in metastatic melanoma was caused by RUNX2 in a transcriptional repression-manner. Conclusion: MiR-23a can act as a crucial epigenetic repressor of melanoma invasion and metastasis in an autophagy-dependent way, which indicates that miR-23a-mediated autophagy inhibition can be exploited to restrain invasion-metastasis cascade in melanoma treatment. Note: This abstract was not presented at the meeting. Citation Format: Weinan Guo, Huina Wang, Yuqi Yang, Sen Guo, Weigang Zhang, Tao Zhao, Lin Liu, Zhe Jian, Ling Liu, Gang Wang, Tianwen Gao, Qiong Shi, Chunying Li. Down-regulated miR-23a contributes to invasion and metastasis of cutaneous melanoma by promoting autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 477. doi:10.1158/1538-7445.AM2017-477
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