Dataset Information

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 H2O2, cell viability was determined in order to identify the most appropriate H2O2 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.

SUBMITTER: Yang C

PROVIDER: S-EPMC6990552 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yang Chao C Yan Zeqiang Z Hu Fen F Wei Wei W Sun Zhihua Z Xu Wei W

Cancer cell international 20200129

<h4>Background</h4>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 ...[more]

PMID: 32015692

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Project description:Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through c-Jun N-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (?H2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators ?H2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS-mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125 ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8-oxoguanine, p-ATM, and ?H2AX were increased compared to those in controls (0 ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis.

Project description:Background & aimsHeat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals.MethodsDouble transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid.ResultsPatients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation.ConclusionsOur results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions.Lay summaryHSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.

Dataset Information

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

Publications

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

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