State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Department of Endocrinology, Tangdu Hospital, Fourth Military Medical University, 710038, Xi'an, Shanxi, China.
Cell Death Dis. 2018 Oct 19;9(11):1070. doi: 10.1038/s41419-018-0950-x.
Multidrug resistance (MDR) accounts for poor prognosis in gastric cancer (GC). MicroRNAs (miRNAs) are critical regulators of MDR via modulation of the target genes. The present study revealed that miR-495-3p could act via a target gene, GRP78, to regulate the process of autophagy and inhibit MDR. Based on the in vitro and in vivo gain-of-function or loss-of-function experiments, overexpression of miR-495-3p was sufficient to reverse the MDR to four chemotherapeutics in vitro and inhibit the tumor growth in vivo. Moreover, GRP78 was positively associated with the occurrence of autophagy. Thus, reducing the expression of GRP78 by siRNA resulted in autophagy-suppressive activity similar to that of miR-495-3p on mammalian target of rapamycin (mTOR) and its substrates activation and autophagy inhibition, while restoring GRP78 attenuated the anti-autophagy effects caused by miR-495-3p. Clinically, either miR-495-3p downregulation or GRP78 upregulation was associated with malignant phenotypes in patients with GC. In conclusion, these findings demonstrate that miR-495-3p is an important regulator of autophagy balance and MDR by modulating the GRP78/mTOR axis. In addition, miR-495-3p and GRP78 could be used as prognostic factors for overall survival in GC, which implicates miR-495-3p as a therapeutic target in cancer.
多药耐药（MDR）是导致胃癌（GC）预后不良的原因。miRNAs（miRNAs）通过调节靶基因在MDR 中起关键调节作用。本研究表明，miR-495-3p 可以通过靶基因 GRP78 发挥作用，调节自噬过程并抑制 MDR。基于体外和体内的功能获得或功能丧失实验，过表达 miR-495-3p 足以在体外逆转四种化疗药物的 MDR 并抑制体内肿瘤生长。此外，GRP78 与自噬的发生呈正相关。因此，通过 siRNA 降低 GRP78 的表达导致自噬抑制活性类似于 miR-495-3p 对哺乳动物雷帕霉素靶蛋白（mTOR）及其底物激活和自噬抑制的作用，而恢复 GRP78 则减弱了 miR-495-3p 引起的抗自噬作用。临床上，GC 患者中 miR-495-3p 的下调或 GRP78 的上调均与恶性表型相关。总之，这些发现表明 miR-495-3p 通过调节 GRP78/mTOR 轴是自噬平衡和 MDR 的重要调节因子。此外，miR-495-3p 和 GRP78 可以用作 GC 总生存期的预后因素，这表明 miR-495-3p 是癌症的治疗靶点。
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