title: A feed-forward loop between lncARSR and YAP activity promotes expansion of renal tumour-initiating cells.
abstract: Renal tumour-initiating cells (T-ICs) contribute to tumorigenesis, progression and drug resistance of renal cell carcinoma (RCC). However, the underlying mechanism for the propagation of renal T-ICs remains unclear. Here we show that long non-coding RNA lncARSR is upregulated in primary renal T-ICs and associated with a poor prognosis of clear cell RCCs (ccRCC). Knockdown of lncARSR attenuates the self-renewal, tumorigenicity and metastasis of renal T-ICs. Conversely, forced lncARSR expression enhances T-IC properties of RCC cells. Mechanistically, the binding of lncARSR to YAP impedes LATS1-induced YAP phosphorylation and facilitates YAP nuclear translocation. Reciprocally, YAP/TEAD promotes lncARSR transcription, thus forming a feed-forward circuit. The correlation between lncARSR and YAP is validated in a ccRCC cohort, where the combination of these two parameters exhibits improved prognostic accuracy. Our findings indicate that lncARSR plays a critical role in renal T-ICs propagation and may serve as a prognostic biomarker and potential therapeutic target.
authors.affiliation: Department of Urology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing 210002, China.|Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Le
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.|Department of Urology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Obstetrics and Gynecology of Navy PLA General Hospital, Beijing 100048, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Dengshuang
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Anbang
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing 210002, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing 210002, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Urology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing 210002, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Linhui
authors.initials: L
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D014157:Transcription Factors; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C000616432:long noncoding RNA ARSR, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases