Abstract 1827: LncRNA TCL6 / microRNA155 axis regulates the PI3K/ AKT pathway in clear cell renal carcinoma

Background: Kidney cancer is among the 10 most common cancers in both men and women, with clear cell carcinoma (ccRCC) being the most common histologic subtype. It has become increasingly apparent that non-coding RNAs are involved in the regulation of a wide variety of diseases. However, the functional role of non-coding RNAs, such as long noncoding RNA (lncRNAs) and microRNAs (miRNA) in the initiation and progression of kidney tumorigenesis is unclear. Here we show an oncogenic role for miR-155-5p in ccRCC and its novel regulation of RCC through LncRNA TCL6. Methods: Profiling of TCL6 and miR-155-5p was performed in microdissected renal cancer tissues, matched adjacent normal regions and in human renal cancer cell lines by quantitative real-time PCR. To assess the functional significance of miR-155-5p in RCC, we generated stable miR-155-5p knockdown RCC cells (786-O, Caki-1) and performed functional assays. We also examined the therapeutic potential of miR-155-5p in vivo using a renal cancer xenograft mouse model injected with these stable cells. We performed qPCR and Western analysis to confirm the interaction between miR-155-5p and its targets (TCL6, PIK3R1, FOXO3a, RhoA). Results: Expression analyses in a cohort of renal cancer clinical specimens showed that LncRNA TCL6 is frequently downregulated and miR-155-5p expression is upregulated in ccRCC. We observed that knockdown of miR-155-5p inhibited cell proliferation, colony formation, migration, invasion and led to G2/M arrest, supporting its oncogenic role in vitro. In ccRCC cells (786-O and Caki-1), inhibition of miR-155-5p significantly upregulated expression, whereas in normal kidney epithelial cell line HK2 over-expression of miR-155-5p decreased levels of its target genes. Over-expression of miR-155-5p in HK2 cells induced cell proliferation, colony formation and enhanced its tumorogenic properties. Furthermore, we found that miR-155-5p may play an important role in the genesis of ccRCC through the PI3K/AKT pathway. In vivo studies demonstrated that the tumor volumes for the mice injected with stable miR-155-5p knockdown cells were significantly less as compared to the mice injected with control parental cells. Conclusions: Collectively, these data suggest that miR-155-5p plays an oncogenic role in ccRCC. These findings offer new insight into role of lncRNA TCL6/miR-155 axis as a key regulator of the PI3K/AKT pathway in the progression of ccRCC. Thus, inhibition of miR-155 may be an effective therapeutic strategy for treating RCC. Citation Format: Priyanka Kulkarni, Pritha Dasgupta, Shahana Majid, Marisa Shiina, Yutaka Hashimoto, Varahram Shahryari, Sharanjot Saini, Soichiro Yamamura, Laura Tabatabai, Guoren Deng, Yuichiro Tanaka, Rajvir Dahiya. LncRNA TCL6 / microRNA155 axis regulates the PI3K/ AKT pathway in clear cell renal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1827.