AB072. A feed forward loop between lncARSR and YAP activity promotes expansion of renal tumor-initiating cells

Background: Renal cell carcinoma (RCC) is the most common kidney cancer in adults prognosis. Increasing appreciation of cell heterogeneity and a challenging disease with poor within clear cell renal cell carcinoma (ccRCC) has focused attention on a distinct subpopulation of cells called tumour initiating cells (T-ICs) or cancer stem cells (CSCs) in ccRCC. T-ICs exhibit extended self-renewal potential and tumour initiating ability. Tumours that harbour an abundant T-IC population or have high expression of stemness-related genes may signal a poor clinical outcome in RCC patients. Therefore, identification of the underlying mechanisms governing renal T-ICs propagation may lead to the discovery of promising therapeutic strategies for RCC patients.

Methods: Long non-coding RNA (lncRNA) is a subgroup of transcripts with more than 200 nt and limited coding potential. lncRNAs modulate biological process via diverse mechanisms, including mobilizing transcriptional co-regulators or chromatin-modifying complex at transcription level, and interacting with RNAs and protein complex or modifying signal proteins at post-transcription level. Several lncRNAs have been reported to regulate the self-renewal of T-ICs especially liver T-ICs. Nevertheless, the role of lncRNA in the regulation of renal T-ICs remains unknown. lncARSR (lncRNA Activated in RCC with Sunitinib Resistance, ENST00000424980) was a newly identified lncRNA to promote the sunitinib resistance of RCC in our previous study. Accumulating evidence indicated that T-ICs surviving from drug therapy and giving rise to tumour regrowth might be a major culprit for therapeutic resistance. Indeed, the expression signature of stem cell or targets of Nanog, Oct4, Sox2 and c-Myc (NOSM) in human ESCs were significantly enriched in our mRNA profile of sunitinib-resistant RCC cells (GSE69535), prompting us to explore the role of lncARSR in renal T-ICs.

Results: In this study, we first find that lncARSR is highly expressed in primary renal T-ICs and predicts poor prognosis. Next, by using loss-of-function analysis in T-ICs and gain-of-function analysis in RCC cells, we demonstrate that lncARSR promotes the self-renewal capacity, tumorigenicity and metastasis of renal T-ICs. Further mechanism study reveals that lncARSR interacts with Yes-associated protein (YAP) to block its phosphorylation by LATS1, facilitating YAP nuclear translocation. Interestingly, we find that YAP in turn promotes the transcription of lncARSR, forming a feed-forward loop. Clinical investigation also confirms the correlation between lncARSR and YAP, and demonstrates the value of combining lncARSR and YAP to improve the prognostic accuracy for RCC patients.

Conclusions: Altogether, we discover that lncARSR promotes the expansion of renal T-ICs via interacting with YAP.

Keywords: Tumour initiating cells (T-ICs); renal cell carcinoma (RCC); Yes-associated protein; lncRNA