RETRACTED ARTICLE: CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p

Abstract

Background: Circular RNAs (circRNAs), a novel type of noncoding RNA (ncRNA), are covalently linked circular configurations that form via a loop structure. Accumulating evidence indicates that circRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise roles of circRNAs in renal cell carcinoma (RCC) remain unknown. Methods: Through circRNA high-throughput sequencing of RCC cell lines, we identified the circRNA TLK1 (circTLK1) as a novel candidate circRNA derived from the TLK1 gene. qRT-PCR detected the mRNA, circRNA and miRNA expression levels in RCC tissues and cells. Loss-of function experiments were executed to detect the biological roles of circTLK1 in the RCC cell phenotypes in vitro and in vivo. RNA-FISH, RNA pull-down, dual-luciferase reporter, western blot and immunohistochemistry assays were used to investigate the molecular mechanisms underlying the functions of circTLK1. Results: circTLK1 is overexpressed in RCC, and expression is positively correlated with distant metastasis and unfavorable prognosis. Silencing circTLK1 significantly inhibited RCC cell proliferation, migration and invasion in vitro and in vivo. circTLK1 was mainly distributed in the cytoplasm and positively regulated CBX4 expression by sponging miR-136-5p. Forced CBX4 expression reversed the circTLK1 suppression-induced phenotypic inhibition of RCC cells. Moreover, CBX4 expression was positively correlated with VEGFA expression in RCC tissues. CBX4 knockdown significantly inhibited VEGFA expression in RCC cells. Conclusion: Collectively, our findings demonstrate that circTLK1 plays a critical role in RCC progression by sponging miR-136-5p to increase CBX4 expression. circTLK1 may act as a diagnostic biomarker and therapeutic target for RCC.

circTLK1 facilitates the proliferation and metastasis of renal cell carcinoma by regulating miR-495-3p/CBL axis

“…In our research, the biological function and potential mechanism of circTLK1 in RCC were investigated in depth. Previous studies revealed that circTLK1 was conspicuously up-regulated in patients with acute ischemic stroke and RCC, which was consistent with the results of this research [ 12 , 21 ]. Besides, loss-of-function experiments indicated that circTLK1 silencing decelerated proliferation and metastasis and facilitated apoptosis in Caki-1 and 786-O cells, which was in agreement with the previous results [ 12 ].…”

“…In non-small cell lung carcinoma, circ_0000376 facilitated tumor progression and elevated chemoresistance via combining with microRNA-384 [ 11 ]. Moreover, a recent study suggested that hsa_circ_0004442 derived from Tousled-like kinases 1 (TLK1) was remarkably up-regulated in RCC, and circTLK1 expedited RCC proliferation and metastasis by modulating microRNA-136-5p/CBX4 pathway [ 12 ]. Nevertheless, the exact mechanism of circTLK1 in RCC development still needs further exploration.…”

Functions of circular RNAs in bladder, prostate and renal cell cancer (Review)

“…Chromobox 4, as a SUMO E3 ligase, upregulates the level of VEGFA, and represses cell growth and metastasis in RCC following circTLK1-silencing or miR-136-5p-overexpression. Circ tousled-like kinase 2 (TLK1; circ_0004442) is derived from the back-splicing of the TLK1 mRNA ( 52 ).…”

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

“…Clinical trials with drugs based on miRNAs have been initiated for different diseases [ 21 ]. In addition, some ncRNAs have been reported as biomarkers for the diagnosis and prognosis of disease or as novel therapeutic targets for cancer intervention [ 22 – 24 ].…”