Abstract
BackgroundPrevious study showed that dsP53-285 has the capacity to induce tumor suppressor gene p53 expression by targeting promoter in non-human primates’ cells. And it is well known that TP53 gene is frequently mutant or inactivated in human bladder cancer. Hereby, whether this small RNA can activate the expression of wild-type p53 and inhibit human bladder cancer cells remains to be elucidated.MethodsOligonucleotide and lentivirus were used to overexpress dsP53-285 and dsControl. Real-time PCR and western blot were used to detect genes’ mRNA and protein expression, respectively. Cell proliferation assay, colony formation, flow cytometry, transwell assay and wound healing assay were performed to determine the effects on bladder cancer cells proliferation and migration/invasion in vitro. Animal models were carried out to analyze the effects on cells growth and metastasis in vivo.ResultsTransfection of dsP53-285 into human bladder cancer cell lines T24 and EJ readily activate wild-type p53 expression by targeting promoter. Moreover, dsP53-285 exhibited robust capacity to inhibit cells proliferation and colony formation, induce cells G0/G1 arrest, suppress migration and invasion. Besides, the Cyclin-CDK genes (Cyclin D1 and CDK4/6) were down-regulated and the EMT-associated genes (E-cadherin, β-catenin, ZEB1 and Vimentin) were also expressed inversely after dsP53-285 treatment. In addition, dsP53-285 could also significantly suppress the growth of bladder cancer xenografts and metastasis in nude mice. Most importantly, the anti-tumor effects mediated by dsP53-285 were mainly achieved by manipulating wild-type p53 expression.ConclusionOur findings indicate that the dsP53-285 can upregulate wild-type p53 expression in human bladder cancer cells through RNA activation, and suppresses cells proliferation and metastasis in vitro and in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0329-8) contains supplementary material, which is available to authorized users.
Highlights
Previous study showed that dsP53-285 has the capacity to induce tumor suppressor gene p53 expression by targeting promoter in non-human primates’ cells
Our results showed that dsP53-285 had potent ability to inhibit bladder cancer cells proliferation and metastasis by modulating wild-type p53 expression
Results dsP53-285 activates wild-type p53 expression by targeting promoter Previous study has identified that a specific double-stranded RNAs (dsRNAs) can induce p53 expression by targeting sequence position -285 relative to the transcription start sites (TSS) in the p53 promoter in African green monkey (COS1) and chimpanzee (WES) cells [12]
Summary
Previous study showed that dsP53-285 has the capacity to induce tumor suppressor gene p53 expression by targeting promoter in non-human primates’ cells. It is well known that TP53 gene is frequently mutant or inactivated in human bladder cancer Hereby, whether this small RNA can activate the expression of wild-type p53 and inhibit human bladder cancer cells remains to be elucidated. Bladder cancer is a major cause of morbidity and mortality worldwide, and with an expected 74,000 newly diagnosed cases and 16,000 deaths in United States in 2015 [1]. Risk factors, such as genetic and molecular abnormalities, chemical or environmental exposures, and chronic irritation, may contribute to the development of bladder cancer [2]. Gain-of-function manipulation of wild-type p53 would be an ideal target for inhibiting bladder cancer cells
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