Ren Hailiang, Wang Zheng, Chen Yao, Liu Yanjun, Zhang Shu, Zhang Tongtong, Li Yuntao
Department of General Surgery, The Third People's Hospital of Chengdu, The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Sichuan, P.R. China,
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing, P.R. China,
Onco Targets Ther. 2019 Apr 8;12:2585-2594. doi: 10.2147/OTT.S186806. eCollection 2019.
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.
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.
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.
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 chemotherapy by SMYD2-OE knockdown in colon cancer treatment.
含SET和MYND结构域蛋白2（SMYD2-OE）通过对组蛋白和非组蛋白进行甲基化修饰，在癌症发展过程中发挥重要作用。然而，关于SMYD2-OE在结肠癌中的相关性知之甚少。此外，奥沙利铂（L-OHP）被用作结肠癌化疗的一线药物，但耐药性限制了其疗效。出人意料的是，结肠癌中L-OHP耐药的机制仍不清楚。在本研究中，我们调查了SMYD2-OE表达与结肠癌中L-OHP耐药性的关系，并进一步探索了连接SMYD2-OE、L-OHP耐药性和结肠癌的潜在机制。
检测患者结肠癌组织中SMYD2-OE的表达水平。进行体外和体内实验，以探索SMYD2-OE在结肠癌对L-OHP敏感性中的作用和机制。
与非肿瘤组织相比，SMYD2-OE在结肠癌组织中过表达，并且与接受基于L-OHP化疗的结肠癌患者的不良预后相关。敲低SMYD2-OE可在体外和体内增加结肠癌对L-OHP的敏感性。然而，SMYD2-OE的过表达在体外促进了结肠癌细胞对L-OHP的耐药性。此外，SMYD2-OE可根据MEK/ERK/AP-1信号通路的活性上调MDR1/P-糖蛋白的表达。
这些结果表明，SMYD2-OE通过MEK/ERK/AP-1信号通路调节MDR1/P-糖蛋白，从而促进结肠癌对L-OHP的耐药性，为在结肠癌治疗中通过敲低SMYD2-OE来提高化疗敏感性提供了一种潜在策略。
