MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer.
MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer.
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MicroRNA-495-3p 通过 GRP78/mTOR 轴调节胃癌中的自噬来抑制多药耐药性。
DOI：
10.1038/s41419-018-0950-x
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发表时间：
2018-10-19
影响因子：
9
通讯作者：
Zhao G
中科院分区：
文献类型：
--
作者：
Chen S;Wu J;Jiao K;Wu Q;Ma J;Chen D;Kang J;Zhao G;Shi Y;Fan D;Zhao G
多药耐药性（MDR）是胃癌（GC）预后不良的原因。 MicroRNA (miRNA) 通过调节靶基因而成为 MDR 的关键调节因子。本研究表明，miR-495-3p可以通过靶基因GRP78调节自噬过程并抑制MDR。基于体外和体内功能获得或功能丧失实验，miR-495-3p的过表达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减少GRP78的表达会导致与miR-495-3p对哺乳动物雷帕霉素靶点（mTOR）及其底物激活和自噬抑制相似的自噬抑制活性，而恢复GRP78会减弱miR-495-3p引起的抗自噬作用。临床上，miR-495-3p 下调或 GRP78 上调与 GC 患者的恶性表型相关。总之，这些发现表明 miR-495-3p 通过调节 GRP78/mTOR 轴而成为自噬平衡和 MDR 的重要调节因子。此外，miR-495-3p和GRP78可以用作GC总体生存的预后因素，这表明miR-495-3p可以作为癌症的治疗靶点。
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.
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影响因子：
21.3
作者：
通讯作者：
--
miR-27a的下调可能会抑制胃癌细胞的增殖和耐药性。
DOI：
10.1186/1756-9966-30-55
发表时间：
2011-05-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Zhao X;Yang L;Hu J
通讯作者：
Hu J
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
21.3
作者：
Cha-Molstad, Hyunjoo;Sung, Ki Sa;Hwang, Joonsung;Kim, Kyoung A.;Yu, Ji Eun;Yoo, Young Dong;Jang, Jun Min;Han, Dong Hoon;Molstad, Michael;Kim, Jung Gi;Lee, Yoon Jee;Zakrzewska, Adriana;Kim, Su-Hyeon;Kim, Sung Tae;Kim, Sun Yong;Lee, Hee Gu;Soung, Nak Kyun;Ahn, Jong Seog;Ciechanover, Aaron;Kim, Bo Yeon;Kwon, Yong Tae
通讯作者：
Kwon, Yong Tae
影响因子：
7.3
作者：
Eun, Jung Woo;Kim, Hyung Seok;Nam, Suk Woo
通讯作者：
Nam, Suk Woo