Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer.
Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer.
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DOI：
10.18632/oncotarget.4937
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发表时间：
2015-10-06
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影响因子：
--
通讯作者：
Sharma D
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文献类型：
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作者：
Avtanski DB;Nagalingam A;Bonner MY;Arbiser JL;Saxena NK;Sharma D
瘦素是一种由脂肪细胞产生的主要脂肪细胞因子，正逐渐成为肥胖与乳腺癌之间的关键分子。因此，寻找有效的策略来拮抗瘦素的致癌作用对阻断肥胖-癌轴具有重要意义。在这里，我们研究和厚朴酚(HNK)作为瘦素拮抗剂的潜力，并系统地阐明其潜在的机制。HNK抑制瘦素诱导的上皮-间充质转化(EMT)和乳房形成，同时下调干细胞因子Oct4和Nanog的表达。研究指导瘦素拮抗剂HNK作用的下游介质S，发现HNK、LKB1和miR-34a之间存在功能上的相互作用。HNK促进LKB1的表达和胞浆定位，而HNK诱导的SIRT1/3增强LKB1的胞浆定位。我们发现，HNK以LKB1依赖的方式增加miR-34a，因为LKB1沉默抑制了HNK诱导的miR-34a，而MIR-34a可以通过LKB1的过表达来挽救。最后，发现miR-34a的完整作用，因为miR-34a模拟加强了HNK介导的对EMT、ZEB1表达和核定位、乳房形成和茎因子表达的抑制。MiR-34a模拟物可进一步增强HNK的瘦素拮抗剂作用，而miR-34a抑制剂则可抑制HNK对瘦素的作用。这些数据为HNK的瘦素拮抗剂潜能提供了证据，并揭示了LKB1和miR-34a的参与。
Leptin, a major adipocytokine produced by adipocytes, is emerging as a key molecule linking obesity with breast cancer therefore, it is important to find effective strategies to antagonize oncogenic effects of leptin to disrupt obesity-cancer axis. Here, we examine the potential of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, as a leptin-antagonist and systematically elucidate the underlying mechanisms. HNK inhibits leptin-induced epithelial-mesenchymal-transition (EMT), and mammosphere-formation along with a reduction in the expression of stemness factors, Oct4 and Nanog. Investigating the downstream mediator(s), that direct leptin-antagonist actions of HNK; we discovered functional interactions between HNK, LKB1 and miR-34a. HNK increases the expression and cytoplasmic-localization of LKB1 while HNK-induced SIRT1/3 accentuates the cytoplasmic-localization of LKB1. We found that HNK increases miR-34a in LKB1-dependent manner as LKB1-silencing impedes HNK-induced miR-34a which can be rescued by LKB1-overexpression. Finally, an integral role of miR-34a is discovered as miR-34a mimic potentiates HNK-mediated inhibition of EMT, Zeb1 expression and nuclear-localization, mammosphere-formation, and expression of stemness factors. Leptin-antagonist actions of HNK are further enhanced by miR-34a mimic whereas miR-34a inhibitor results in inhibiting HNK's effect on leptin. These data provide evidence for the leptin-antagonist potential of HNK and reveal the involvement of LKB1 and miR-34a.