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MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.

ABSTRACT: miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-?B activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.

SUBMITTER: Mai S

PROVIDER: S-EPMC6817863 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.

Mai ShiJuan S Xiao RuoWen R Shi Lu L Zhou XiaoMin X Yang Te T Zhang MeiYin M Weng NuoQing N Zhao XinGe X Wang RuiQi R Liu Ji J Sun Rui R Qin HaiDe H Wang HuiYun H

Cell death & disease 20191028 11

miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ecto ...[more]

PMID: 31659158

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Project description:BackgroundEndometrial carcinoma (EC) is one of the most common gynecological malignancies among women. Maternal embryonic leucine Zipper Kinase (MELK) is upregulated in a variety of human tumors, where it contributes to malignant phenotype and correlates with a poor prognosis. However, the biological function of MELK in EC progression remains largely unknown.MethodsWe explored the MELK expression in EC using TCGA and GEO databases and verified it using clinical samples by IHC methods. CCK-8 assay, colony formation assay, cell cycle assay, wound healing assay and subcutaneous xenograft mouse model were generated to estimate the functions of MELK and its inhibitor OTSSP167. qRT-PCR, western blotting, co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanism concerning MELK during the progression of EC.FindingsMELK was significantly elevated in patients with EC, and high expression of MELK was associated with serous EC, high histological grade, advanced clinical stage and reduced overall survival and disease-free survival. MELK knockdown decreased the ability of cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. In addition, high expression of MELK could be regulated by transcription factor E2F1. Moreover, we found that MELK had a direct interaction with MLST8 and then activated mTORC1 and mTORC2 signaling pathway for EC progression. Furthermore, OTSSP167, an effective inhibitor, could inhibit cell proliferation driven by MELK in vivo and vitro assays.InterpretationWe have explored the crucial role of the E2F1/MELK/mTORC1/2 axis in the progression of EC, which could be served as potential therapeutic targets for treatment of EC.FundingThis research was supported by National Natural Science Foundation of China (No:81672565), the Natural Science Foundation of Shanghai (Grant NO:17ZR1421400 to Dr. Zhihong Ai) and the fundamental research funds for central universities (No: 22120180595).

Dataset Information

MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.

Publications

MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma.

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