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

Authors Wang JH, Wang W, Li JC, Wu LJ, Song M, Meng QG

Received 8 September 2016

Accepted for publication 18 December 2016

Published 7 February 2017 Volume 2017:10 Pages 667—679


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ashok Kumar Pandurangan

Peer reviewer comments 2

Editor who approved publication: Dr Jianmin Xu

Jinhui Wang,1,* Wei Wang,2,* Jichen Li,2 Liji Wu,2 Mei Song,1 Qinggang Meng3

1Department of Clinical Laboratory, Harbin First Hospital, 2Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, 3Department of Osteological Surgery, Harbin First Hospital, Harbin, People’s Republic of China

*These authors contributed equally to this work

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.

Keywords: miR182, Ras–MEK–ERK, RASA1, SPRED1, OSCC

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