MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer

被引：257

作者：

He, Wanming ^{[1
]}

Liang, Bishan ^{[1
]}

Wang, Chunlin ^{[1
]}

Li, Shaowei ^{[1
]}

Zhao, Yang ^{[1
]}

Huang, Qiong ^{[1
]}

Liu, Zexian ^{[2
]}

Yao, Zhiqi ^{[1
]}

Wu, Qijing ^{[1
]}

Liao, Wangjun ^{[1
]}

Zhang, Shuyi ^{[1
]}

Liu, Yajing ^{[1
]}

Xiang, Yi ^{[1
]}

Liu, Jia ^{[1
]}

Shi, Min ^{[1
]}

机构：

[1] Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou, Guangdong, Peoples R China

来源：

ONCOGENE | 2019年 / 38卷 / 23期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

TGF-BETA; DRUG-RESISTANCE; CELLS; MECHANISMS; CHEMOTHERAPY; METASTASIS; METABOLISM; SURVIVAL;

D O I：

10.1038/s41388-019-0747-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients and chemotherapy resistance is the major obstacle to effective cancer therapy. Increasing evidence suggests that mesenchymal stem cells (MSCs) make important contributions to development of drug resistance. However, the underlying mechanism remains elusive. In this study, we discovered that abundant MSCs in tumor tissues predicted a poor prognosis in GC patients. MSCs promoted stemness and chemoresistance in GC cells through fatty acid oxidation (FAO) in vitro and in vivo. Mechanically, transforming growth factor beta 1 (TGF-beta 1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (lncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p. Moreover, pharmacologic inhibition of FAO with etomoxir (ETX) attenuated MSC-induced FOLFOX regiment resistance in vivo. These results suggest that FAO plays an important role in MSC-mediated stemness and chemotherapy resistance in GC and FAO inhibitors in combination with chemotherapeutic drugs present as a promising strategy to overcome chemoresistance.

引用

页码：4637 / 4654

页数：18

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