LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma

• Published in: Cell death & disease Vol. 11; no. 8; p. 660
• Main Authors: Dasgupta, Pritha, Kulkarni, Priyanka, Majid, Shahana, Hashimoto, Yutaka, Shiina, Marisa, Shahryari, Varahram, Bhat, Nadeem S., Tabatabai, Laura, Yamamura, Soichiro, Saini, Sharanjot, Tanaka, Yuichiro, Dahiya, Rajvir
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2020; Springer Nature B.V
• Subjects: 13; 13/106; 13/109; 13/2; 13/31; 13/89; 38; 38/39; 38/77; 38/90; 631/67/322; 631/67/589; 82; 82/1; 82/80; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Binding sites; Biochemistry; Biomedical and Life Sciences; Carcinogenesis - genetics; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cyclin D; Cyclin D - genetics; Cyclin D - metabolism; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin D2 - genetics; Cyclin D2 - metabolism; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Disease Progression; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic - genetics; Humans; Immunology; Immunoprecipitation; Kidney cancer; Life Sciences; Male; Mesenchyme; Metastases; Metastasis; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Metastasis - genetics; Rac1 protein; Renal cell carcinoma; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Therapeutic applications; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02877-0

The molecular heterogeneity of renal cell carcinoma (RCC) complicates the therapeutic interventions for advanced metastatic disease and thus its management remains a significant challenge. This study investigates the role of the lncRNA CDKN2B-AS1 and miR-141-3p interactions in the progression and metastasis of kidney cancer. Human renal cancer cell lines (ACHN and Caki1), normal RPTEC cells, tissue cohorts, and a series of in vitro assays and in vivo mouse model were used for this study. An overexpression of CDKN2B-AS1 was observed in RCC compared to normal samples in TCGA and our in-house SFVAMC tissue cohorts. Reciprocally, we observed reduced expression of miR-141 in RCC compared to normal in the same cohorts. CDKN2B-AS1 shares regulatory miR-141 binding sites with CCND1 and CCND2 genes. Direct interactions of CDKN2B-AS1 /miR-141/Cyclin D1–D2 were confirmed by RNA immunoprecipitation and luciferase reporter assays indicating that CDKN2B-AS1 /miR-141/Cyclin D1–D2 acts as a ceRNA network in RCC. Functionally, attenuation of CDKN2B-AS1 and/or overexpression of miR-141 inhibited proliferation, clonogenicity, migration/invasion, induced apoptosis in vitro and suppressed tumor growth in xenograft mouse model. Further, overexpression of CDKN2B-AS1 is positively correlated with poor overall survival of RCC patients. Expression of miR-141 also robustly discriminated malignant from non-malignant tissues and its inhibition in normal RPTEC cells induced pro-cancerous characteristics. CDKN2B-AS1 attenuation or miR-141 overexpression decreased CCND1/CCND2 expression, resulting in reduced RAC1/pPXN that are involved in migration, invasion and epithelial–mesenchymal transition. This study, for the first time, deciphered the role of CDKN2B-AS1 /miR-141/Cyclin D axis in RCC and highlights this network as a promising therapeutic target for the regulation of EMT driven metastasis in RCC.