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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / mortality
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Carcinoma, Renal Cell / pathology*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cohort Studies
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Disease Progression
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Female
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Gene Knockdown Techniques
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Humans
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Kidney / pathology
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Kidney Neoplasms / genetics
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Kidney Neoplasms / mortality
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Kidney Neoplasms / pathology*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Neoplastic Stem Cells / cytology
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Phosphorylation
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Prognosis
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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Survival Analysis
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Transcription Factors
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Up-Regulation
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Biomarkers, Tumor
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Phosphoproteins
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RNA, Long Noncoding
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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long noncoding RNA ARSR, human
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LATS1 protein, human
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Protein Serine-Threonine Kinases
Supplementary concepts
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Clear-cell metastatic renal cell carcinoma