Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Le Qu; Jin Ding; Cheng Chen; Zhen-Jie Wu; Bing Liu; Yi Gao; Wei Chen; Feng Liu; Wen Sun; Xiao-Feng Li; Xue Wang; Yue Wang; Zhen-Yu Xu; Li Gao; Qing Yang; Bin Xu; Yao-Ming Li; Zi-Yu Fang; Zhi-Peng Xu; Yi Bao; Deng-Shuang Wu; Xiong Miao; Hai-Yang Sun; Ying-Hao Sun; Hong-Yang Wang; Lin-Hui Wang

doi:10.1016/j.ccell.2016.03.004

Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Cancer Cell. 2016 May 9;29(5):653-668. doi: 10.1016/j.ccell.2016.03.004. Epub 2016 Apr 21.

Authors

Le Qu¹, Jin Ding², Cheng Chen³, Zhen-Jie Wu¹, Bing Liu¹, Yi Gao¹, Wei Chen¹, Feng Liu⁴, Wen Sun², Xiao-Feng Li², Xue Wang², Yue Wang⁵, Zhen-Yu Xu⁵, Li Gao⁶, Qing Yang⁷, Bin Xu⁷, Yao-Ming Li⁷, Zi-Yu Fang⁷, Zhi-Peng Xu¹, Yi Bao¹, Deng-Shuang Wu¹, Xiong Miao⁸, Hai-Yang Sun⁹, Ying-Hao Sun⁷, Hong-Yang Wang¹⁰, Lin-Hui Wang¹¹

Affiliations

¹ Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
² The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
³ The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; Department of Medical Oncology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing 210002, China.
⁴ Department of Medical Genetics, College of Basic Medicine, Second Military Medical University, Shanghai 200433, China.
⁵ Department of Histology and Embryology, College of Basic Medicine, Second Military Medical University, Shanghai 200433, China.
⁶ Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
⁷ Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
⁸ Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
⁹ Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
¹⁰ The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: hywangk@vip.sina.com.
¹¹ Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. Electronic address: wanglinhuicz@163.com.

PMID: 27117758
DOI: 10.1016/j.ccell.2016.03.004

Abstract

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Axl Receptor Tyrosine Kinase
Blotting, Northern
Carcinoma, Renal Cell / blood
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / genetics
Cell Line
Cell Line, Tumor
Disease-Free Survival
Drug Resistance, Neoplasm / genetics*
Exosomes / genetics*
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Humans
Indoles / pharmacology*
Kidney Neoplasms / blood
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / genetics
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-met / genetics
Pyrroles / pharmacology*
RNA, Long Noncoding / blood
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
Receptor Protein-Tyrosine Kinases / genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Sunitinib
Treatment Outcome
Xenograft Model Antitumor Assays / methods

Substances

Antineoplastic Agents
Indoles
MIRN34 microRNA, human
MIRN449 microRNA, human
MicroRNAs
Proto-Oncogene Proteins
Pyrroles
RNA, Long Noncoding
RNA, Neoplasm
long noncoding RNA ARSR, human
Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases
Sunitinib
Axl Receptor Tyrosine Kinase