Silencing of microRNA-517a induces oxidative stress injury in melanoma cells via inactivation of the JNK signaling pathway by upregulating CDKN1C

Abstract

Background: Melanoma is notoriously resistant to current treatments, and less than 25% of metastatic melanoma cases respond to existing therapies. Growing evidence has shown that microRNAs (miRNAs) play a vital role in the prognosis of melanoma. MiR-517a has been implicated in many types of cancer; however, its expressional features and potential biological functions in melanoma remain unclear. The present study aimed to investigate the possible effects of miR-517a on oxidative stress (OS) in melanoma cells. Methods: miR-517a expression in melanoma was determined using RT-qPCR. After treatment with different concentrations of H 2 O 2 , cell viability was determined in order to identify the most appropriate H 2 O 2 concentration. Through loss and gain of function experiments, the interactions between miR-517a, the cyclin dependent kinase inhibitor 1C (CDKN1C) and the c-Jun NH2-terminal kinase (JNK) signaling pathway, as well as their roles in OS of melanoma cells were identified. Moreover, the expression of Cleaved Caspase-3, extent of ERK1/2 phosphorylation, Bax/Bcl-2 ratio, levels of T-AOC, ROS and MDA, and SOD activity were also tested. Finally, melanoma cell viability and apoptosis were detected. Results: MiR-517a was upregulated, while CDKN1C was downregulated in melanoma tissues and cells. MiR-517a targets CDKN1C and consequently reduced its expression. Inhibition of miR-517a was shown to increase Cleaved Caspase-3 expression, Bax/Bcl-2 ratio, levels of ROS and MDA, as well as cell apoptosis but decrease extent of ERK1/2 phosphorylation, T-AOC levels, SOD activity, along with cell proliferation and mitochondrial membrane potential. Conclusions: Overall, silencing miR-517a results in upregulated CDKN1C expression, and inhibited JNK signaling pathway activation, consequently promoting OS in melanoma cells.

miR-541 serves as a prognostic biomarker of osteosarcoma and its regulatory effect on tumor cell proliferation, migration and invasion by targeting TGIF2

“…Recently, the role of miRNAs in the progression of various human malignancies has attracted huge attention [16,17]. More and more miRNAs have been reported to be associated with the occurrence of tumor, especially the miRNAs with abnormal expression [18,19]. For example, miR-125 was upregulated in colorectal cancer, and it exerted inhibitory effects on the proliferation and invasion of colorectal cancer cells [20].…”

miR-517b-3p promotes the progression of portal vein tumor thrombus via activating Wnt/β-catenin signaling pathway in hepatocellular carcinoma

“…The increased expression of miR-517a was also been reported in melanoma. Silencing the expression of microrna-517a can upregulate the expression of CDKN1C, inactivate JNK signaling pathway and induce oxidative stress injury of melanoma cells (Yang et al 2020). In HCC, miR-517a has been described as an oncogene with its signi cant elevated expression in tumor tissues (Toffanin et al 2011).…”

Regulation of miRNAs Expression by Mutant p53 Gain of Function in Cancer

“…cyclin/cyclin-dependent kinase complexes), cleaved caspase-3, Bax/Bcl2 ratio, as well as high levels of Reactive Oxidative Species (ROS) and diminished cell proliferation (Yang et al, 2020). It is important to note that these reports do not clarify how miR-517a induces the aforementioned effects; meanwhile, other authors have been approaching identifying some of its targets.…”

“…Moreover, knockdown of miR-517a in glioma cells led to diminished cell proliferation and higher apoptosis; then, using a cell-line-derived xenograft mouse model, the U87 glioma cells lines expressing sh-miR-517a, showed lesser tumor growth as compared to the wild type cells ( Du et al, 2019 ). Likewise, the silencing of miR-517a in melanoma cells induced up-regulation of CDKN1C (inhibitor of cyclin/cyclin-dependent kinase complexes), cleaved caspase-3, Bax/Bcl2 ratio, as well as high levels of Reactive Oxidative Species (ROS) and diminished cell proliferation ( Yang et al, 2020 ). It is important to note that these reports do not clarify how miR-517a induces the aforementioned effects; meanwhile, other authors have been approaching identifying some of its targets.…”