BackgroundCircular RNA (circRNA) is a type of circular endogenous RNA produced by special selective splicing and participates in progression of diverse diseases. However, the role of circRNA in clear cell renal cell carcinoma (ccRCC) is still rarely reported.MethodsWe detected lower circ-AKT3 expression in ccRCC using the circular RNA microarray. Then, qPCR array was applied to verify the expression of circ-AKT3 in between 60 ccRCC tissues and adjacent normal tissues, as well as ccRCC cell lines and human normal kidney cell (HK-2). We investigated the function of circ-AKT3 in ccRCC in vitro and in vivo and detected underlying mechanisms by Western blotting, bioinformatic analysis, RNA pull-down assay and luciferase reporter assay.ResultsCirc-AKT3 was verified significantly downregulated in ccRCC. Knockdown of circ-AKT3 promoted ccRCC migration and invasion, while overexpression of circ-AKT3 suppressed ccRCC metastasis. Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis.ConclusionCirc-AKT3 suppresses ccRCC metastasis by enforcing E-cadherin expression through competitively binding miR-296-3p. Circ-AKT3 may therefore serve as a novel therapeutic to better suppress ccRCC metastasis.

Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m 6 A) is implicated in various stages of cancer development. However, a thorough understanding of m 6 A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. Highthroughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m 6 A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m 6 A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m 6 A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m 6 A and lncRNA in ccRCC for the first time.

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