Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, 100050, Beijing, China.
State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, 102206, Beijing, China.
Cell Death Dis. 2019 Feb 15;10(3):153. doi: 10.1038/s41419-019-1326-6.
Despite gemcitabine being the leading chemotherapeutic drug for pancreatic cancer, many patients still relapse due to the drug resistance. We previously reported the molecular link between FKBP51 mediated AKT inhibition and gemcitabine response in pancreatic cancers. However, the upstream regulator of this pathway, especially the involvement of non-coding RNAs in gemcitabine response is still not clear. Here we delineated the miRNA expression profile and key signaling pathways associated with gemcitabine response. Furthermore, we confirmed that miR-30a, one node of this network, regulated cellular response to gemcitabine through SNAI1-IRS1-AKT pathway. MiR-30a directly targeted SNAI1, which activates AKT and ERK through regulating IRS1 in vitro and in vivo. Clinically, miR-30a is downregulated in pancreatic cancer tissue and associated with overall patient survival. We also identified miR-30a as an AKT-FOXO3a-regulated gene that forms a feedback loop. Together, these results demonstrate that miR-30a is an upstream regulator of the Akt pathway with a critical role in cancer etiology and chemoresistance.
尽管吉西他滨是胰腺癌的主要化疗药物，但许多患者仍因耐药而复发。我们之前报道了 FKBP51 介导的 AKT 抑制与胰腺癌中吉西他滨反应之间的分子联系。然而，该通路的上游调节剂，特别是非编码 RNA 在吉西他滨反应中的参与仍不清楚。在这里，我们描绘了与吉西他滨反应相关的 miRNA 表达谱和关键信号通路。此外，我们证实了该网络中的一个节点 miR-30a 通过 SNAI1-IRS1-AKT 通路调节细胞对吉西他滨的反应。miR-30a 直接靶向 SNAI1，通过调节 IRS1 在体外和体内激活 AKT 和 ERK。临床上，miR-30a 在胰腺癌组织中下调，并与患者的总生存相关。我们还确定 miR-30a 是 AKT-FOXO3a 调节基因的一个靶点，形成一个反馈回路。总之，这些结果表明 miR-30a 是 Akt 通路的上游调节剂，在癌症发病机制和化疗耐药性中起着关键作用。
