Metastasis is the leading cause of mortality from kidney cancer, and understanding the underlying mechanism of this event will provide better strategies for its management. Here we investigated the biological, functional, and clinical significance of lncTCL6 and its interacting miR-155 in clear cell renal cell carcinoma (ccRCC). We employed a comprehensive approach to investigate the lncTCL6-miR155-Src/Akt-mediated EMT pathway as a novel regulatory mechanism in ccRCC progression. Expression analyses revealed that lncTCL6 is downregulated in ccRCC compared to normal tissues. Overexpression of lncTCL6 in ccRCC cell lines impaired their oncogenic functions such as cell proliferation and migration/invasion and induced cell cycle arrest and apoptosis; conversely, depletion of lncTCL6 rescued these phenotypic effects. Furthermore, lncTCL6 directly interacted with miR-155. Unlike lncTCL6, miR-155 was overexpressed in ccRCC. Stable knockdown of miR-155 phenocopied the effects of lncTCL6 overexpression. Conversely, reconstitution of miR-155 and suppression of lncTCL6 in non-cancerous renal cell HK2 induced tumorigenic characteristics. Patients with higher expression of lncTCL6 and lower expression of miR-155 had better survival probability. When overexpressed, lncTCL6 recruited STAU1 and mediated decay of Src mRNA, followed by a marked downregulation of an integrated network of Src target genes involved in migration, invasion, and EMT. However, the interaction between miR-155 and lncTCL6 attenuated the regulatory role of lncTCL6 on Src-mediated EMT. In conclusion, this study is the first report documenting the lncTCL6-miR155-Src/Akt/EMT network as a novel regulatory mechanism in aggressive ccRCC and a promising therapeutic target to inhibit renal cancer.
Cancer research. 2021 Jan 26 [Epub ahead of print]
Priyanka Kulkarni, Pritha Dasgupta, Yutaka Hashimoto, Marisa Shiina, Varahram Shahryari, Z Laura Tabatabai, Soichiro Yamamura, Yuichiro Tanaka, Sharanjot Saini, Rajvir Dahiya, Shahana Majid
Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco., Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco., Department of Pathology, San Francisco Veterans Affairs Medical Center and University of California San Francisco., Biochemistry and Molecular Biology, Augusta University., Department of Urology, University of California San Francisco (UCSF) and VAMC San Francisco., Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco .