Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA.
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.
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Le
L
Qu
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
Jin
J
Ding
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.
Cheng
C
Chen
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Zhen-Jie
ZJ
Wu
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Bing
B
Liu
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Yi
Y
Gao
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Wei
W
Chen
Department of Medical Genetics, College of Basic Medicine, Second Military Medical University, Shanghai 200433, China.
Feng
F
Liu
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
Wen
W
Sun
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
Xiao-Feng
XF
Li
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
Xue
X
Wang
Department of Histology and Embryology, College of Basic Medicine, Second Military Medical University, Shanghai 200433, China.
Yue
Y
Wang
Department of Histology and Embryology, College of Basic Medicine, Second Military Medical University, Shanghai 200433, China.
Zhen-Yu
ZY
Xu
Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Li
L
Gao
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Qing
Q
Yang
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Bin
B
Xu
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Yao-Ming
YM
Li
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Zi-Yu
ZY
Fang
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Zhi-Peng
ZP
Xu
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Yi
Y
Bao
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Deng-Shuang
DS
Wu
Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Xiong
X
Miao
Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
Hai-Yang
HY
Sun
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Ying-Hao
YH
Sun
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: hywangk@vip.sina.com.
Hong-Yang
HY
Wang
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. Electronic address: wanglinhuicz@163.com.
Lin-Hui
LH
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055354:Exosomes / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology*; D062085:RNA, Long Noncoding / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000077210:Sunitinib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000094963:Axl Receptor Tyrosine Kinase
D000970:Antineoplastic Agents; D007211:Indoles; C522425:MIRN34 microRNA, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; C000616432:long noncoding RNA ARSR, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; D000094963:Axl Receptor Tyrosine Kinase