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

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

Author information

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.

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.

PMID:
27117758
DOI:
10.1016/j.ccell.2016.03.004
[Indexed for MEDLINE]
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