长链非编码 RNA MALAT1 通过 miR-23b-3p 的海绵作用调控胃癌自噬相关化疗耐药性。
Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer.
机构信息
Department of General Surgery, The third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang, China.
Department of Gastroenterology, The third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang, China.
出版信息
Mol Cancer. 2017 Nov 21;16(1):174. doi: 10.1186/s12943-017-0743-3.
BACKGROUND
Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient's response to chemotherapeutics.
METHODS
lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance.
RESULTS
We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells.
CONCLUSIONS
Taken together, our study revealed a novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance.
背景
化疗耐药性长期以来一直被认为是癌症治疗的主要障碍。阐明化疗耐药性的潜在机制将产生新的策略来提高患者对化疗药物的反应。
方法
通过实时定量 PCR（qPCR）检测胃癌（GC）细胞中的 lncRNA 表达水平。将 MALAT1 shRNA 和过表达载体转染到 GC 细胞中，下调或上调 MALAT1 的表达。进行体外和体内实验来研究 MALAT1 在自噬相关化疗耐药性中的功能作用。
结果
我们发现与亲本细胞相比，耐药性 GC 细胞中 MALAT1 水平更高且自噬增加。沉默 MALAT1 抑制了化疗诱导的自噬，而 MALAT1 促进了胃癌细胞的自噬。下调 MALAT1 可使 GC 细胞对化疗药物敏感。MALAT1 作为 miR-23b-3p 的竞争性内源性 RNA，减弱了 miR-23b-3p 对 ATG12 的抑制作用，导致 GC 细胞中化疗诱导的自噬和化疗耐药性。
结论
综上所述，我们的研究揭示了 lncRNA 调控的自噬相关化疗耐药性的新机制，为理解化疗耐药性提供了新的思路。
Zotero 插件