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MiR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1.

ABSTRACT: PURPOSE:The constitutive activation of the Ras-MEK-ERK signaling pathway in oral cavity squamous cell carcinoma (OSCC) has been found to be tightly controlled at multiple levels under physiological conditions. RASA1 and SPRED1 are two important negative regulators of this pathway, but the exact regulating mechanism remains unclear. In this study, we aimed to explore the potential regulating mechanisms involved in the Ras-MEK-ERK signaling pathway in OSCC. MATERIALS AND METHODS:MicroRNA (miRNA) expression was detected by quantitative reverse-transcription polymerase chain reaction. The protein levels of RASA1, SPRED1, and signaling proteins were detected by Western blot. Cell growth was determined using CCK-8 reagent, colony formation was stained by crystal violet, and cell invasion was tested using transwell chambers. Cell apoptosis and the cell cycle were then analyzed by flow cytometry. The binding of miR182 with RASA1 or SPRED1 was evaluated by luciferase reporter assays on a dual-luciferase reporter system. RESULTS:The expression of miR182 was found to be upregulated significantly in malignant oral carcinoma tissues compared with the adjacent nonmalignant tissues, and was inversely correlated with protein levels of RASA1 and SPRED1. Overexpression of miR182 in OSCC cell lines sustained Ras-MEK-ERK signaling-pathway activation, and promoted cell proliferation, cell-cycle progression, colony formation, and invasion capacity, whereas miR182 downregulation alleviated these properties significantly in vitro. Furthermore, we demonstrated that miR182 exerted its oncogenic role in OSCC by directly targeting and suppressing RASA1 and SPRED1. CONCLUSION:Our results bring new insights into the important role of miR182 in the activation of the Ras-MEK-ERK signaling pathway, and suggest that miR182 may be used as a potential target for treatment of OSCC, prompting further investigation into miRNA antisense oligonucleotides for cancer therapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC5308578 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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miR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1.

Wang Jinhui J Wang Wei W Li Jichen J Wu Liji L Song Mei M Meng Qinggang Q

OncoTargets and therapy 20170207

<h4>Purpose</h4>The constitutive activation of the Ras-MEK-ERK signaling pathway in oral cavity squamous cell carcinoma (OSCC) has been found to be tightly controlled at multiple levels under physiological conditions. RASA1 and SPRED1 are two important negative regulators of this pathway, but the exact regulating mechanism remains unclear. In this study, we aimed to explore the potential regulating mechanisms involved in the Ras-MEK-ERK signaling pathway in OSCC.<h4>Materials and methods</h4>Mic ...[more]

PMID: 28223824

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Project description:The enhanced migratory ability of endometrial stromal cells (ESCs) is a key factor in the formation of functional endometrium‑like tissues outside the uterine cavity during endometriosis (EMS). Although accumulating evidence has suggested the importance of microRNAs (miRNAs) in the pathogenesis of EMS, the role of particular miRNAs in the invasiveness of ESCs remain poorly understood. In the present study, the function of miRNAs in the invasiveness of ESCs, along with the associated underlying mechanism involved, were investigated. Initially, the expression patterns of miRNAs in the ectopic and eutopic endometrium isolated from patients with EMS were analyzed using microarray. MicroRNA‑202‑5p (miR‑202) was selected for further study due to its previously reported suppressive effects on the invasion in various types of cancers. The expression of miR‑202 and K‑Ras in eutopic and ectopic endometrioma tissues were detected using reverse transcription‑quantitative PCR, immunohistochemistry and western blotting. The migration and invasion ability of ESCs was determined using wound healing and Transwell invasion assays, respectively. Compared with that from healthy individuals, miR‑202 expression was demonstrated to be lower in the eutopic endometrium from patients with EMS, which was even lower in ectopic endometrium. Functional experiments in primary ESCs revealed that enhanced miR‑202 expression suppressed the cell invasion and migration abilities, which was also accompanied with increased E‑cadherin and reduced N‑cadherin expression in ESCs, suggesting its potentially suppressive role in epithelial‑mesenchymal transition. K‑Ras is a well‑known regulator of the ERK signaling pathway that was shown to be directly targeted and negatively regulated by miR‑202. In addition, K‑Ras expression was found to be upregulated in the ectopic endometrium, where it correlated negatively with that of miR‑202. Knocking down K‑Ras expression mimicked the anti‑invasive effects of miR‑202 overexpression on ESCs, whilst K‑Ras overexpression attenuated the inhibitory role of miR‑202 overexpression in ESC invasion. The K‑Ras/Raf1/MEK/ERK signaling pathway was also blocked by miR‑202 overexpression. These findings suggested that miR‑202 inhibited ESC migration and invasion by inhibiting the K‑Ras/Raf1/MEK/ERK signaling pathway, rendering miR‑202 a candidate for being a therapeutic target for EMS.

Dataset Information

MiR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1.

Publications

miR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1.

Similar Datasets

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