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SMYD2-OE promotes oxaliplatin resistance in colon cancer through MDR1/P-glycoprotein via MEK/ERK/AP1 pathway

Authors Ren H, Wang Z, Chen Y, Liu Y, Zhang S, Zhang T, Li Y

Received 7 September 2018

Accepted for publication 24 January 2019

Published 8 April 2019 Volume 2019:12 Pages 2585—2594

DOI https://doi.org/10.2147/OTT.S186806

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Justinn Cochran

Peer reviewer comments 3

Editor who approved publication: Dr Sanjay Singh


Hailiang Ren,1,* Zheng Wang,2,* Yao Chen,3 Yanjun Liu,1 Shu Zhang,1 Tongtong Zhang,2 Yuntao Li1

1Department of General Surgery, The Third People’s Hospital of Chengdu, The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Sichuan, P.R. China; 2State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing, P.R. China; 3West China Hospital, Sichuan University, Wuhou District, Chengdu, P.R. China

*These authors contributed equally to this work

Background: SET and MYND domain-containing protein 2 (SMYD2-OE) plays an important role in cancer development through methylating histone and non-histone proteins. However, little is known about the relevance of SMYD2-OE in colon cancer. Moreover, oxaliplatin (L-OHP) is applied as first line for colon cancer chemotherapy, but drug resistance restricts its efficacy. Unexpectedly, the mechanism of L-OHP resistance in colon cancer remains unclear. In this study, we investigated the relationship of SMYD2-OE expression and L-OHP resistance in colon cancer and further explored the underlying mechanism linking SMYD2-OE, L-OHP resistance, and colon cancer.
Materials and methods: Expression levels of SMYD2-OE in colon cancer tissues of patients were tested. In vitro and in vivo assays were conducted to explore the function and mechanism of SMYD2-OE in colon cancer sensitivity to L-OHP.
Results: SMYD2-OE was overexpressed in colon cancer tissues compared with non-neoplastic tissues and associated with poor prognosis of patients with colon cancer after L-OHP-based chemotherapy. Knockdown of SMYD2-OE increased colon cancer sensitivity to L-OHP in vitro and in vivo. However, SMYD2-OE overexpression promoted L-OHP resistance in colon cancer cell in vitro. In addition, SMYD2-OE could upregulate MDR1/P-glycoprotein expression depending on MEK/ERK/AP-1 signaling pathway activity.
Conclusion: These results imply that SMYD2-OE promotes L-OHP resistance in colon cancer by regulating MDR1/P-glycoprotein through MEK/ERK/AP-1 signaling pathway, providing a potential strategy to sensitize che-motherapy by SMYD2-OE knockdown in colon cancer treatment.

Keywords: SMYD2-OE, oxaliplatin resistance, colon cancer, MEK/ERK/AP-1 signaling pathway


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