Role of N<sup>6</sup>-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer

Zhang Shihui; Qi Qiuchen; Li Peilong; Du Lutao; Wang Chuanxin

doi:10.13406/j.cnki.cyxb.003077

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Role of N⁶-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer

Precise targeting—tumor | 更新时间：2025-10-21

- Role of N⁶-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer
- Journal of Chongqing Medical University Vol. 47, Issue 8, Pages: 941-947(2022)
- 作者机构：
  
  山东大学第二医院检验医学中心、山东省肿瘤标志物检测工程实验室，济南 250033
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003077
  CLC： R735.3
- Received：01 June 2022，
  
  Published：28 August 2022
- 稿件说明：
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张世慧,齐秋晨,李培龙,等.METTL3介导的m⁶A修饰在结直肠癌奥沙利铂耐药中的作用研究[J].重庆医科大学学报,2022,47(8):941-947.

Zhang Shihui,Qi Qiuchen,Li Peilong,et al.Role of N⁶-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer[J].Journal of Chongqing Medical University,2022,47(8):941-947.
张世慧,齐秋晨,李培龙,等.METTL3介导的m⁶A修饰在结直肠癌奥沙利铂耐药中的作用研究[J].重庆医科大学学报,2022,47(8):941-947. DOI： 10.13406/j.cnki.cyxb.003077.

Zhang Shihui,Qi Qiuchen,Li Peilong,et al.Role of N⁶-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer[J].Journal of Chongqing Medical University,2022,47(8):941-947. DOI： 10.13406/j.cnki.cyxb.003077.

摘要

目的

探究N

-甲基腺嘌呤（N

-methyladenosine，m

A）调控因子甲基转移酶样蛋白3（methyltransferase-like 3，METTL3）在结直肠癌奥沙利铂（oxaliplatin，OXA）耐药中的作用。

方法

采用浓度梯度法构建OXA耐药细胞株HCT116/OXA，CCK-8分析其耐药性；采用Dot blot及m

A RNA甲基化定量ELISA实验检测细胞RNA m

A水平，RNA-seq及qRT-PCR筛选差异m

A调控因子，Western blot验证METTL3表达水平；利用腺病毒感染技术在HCT116细胞过表达METTL3，CCK-8检测各组细胞的增殖活性；通过对GEO数据库中HCT116细胞敲除METTL3的MeRIP-seq和RNA-seq数据与耐药细胞RNA-seq联合分析，筛选耐药相关的METTL3介导m

A修饰调控的下游靶基因及信号通路；TCGA数据库分析METTL3与患者预后的相关性。

结果

HCT116/OXA细胞对OXA的耐药性明显高于其亲代细胞（

0.01）；与HCT116相比，耐药细胞的RNA m

A水平异常上调（

0.01），且伴随METTL3的mRNA和蛋白水平升高；过表达METTL3明显增强HCT116细胞对OXA的耐药性（

0.01）；多组学数据联合分析筛选的METTL3介导m

A修饰调控的与耐药相关的关键基因主要富集在ABC转运蛋白、干细胞多能性调节信号通路、TGF-β信号通路等；METTL3高表达与结直肠癌患者的不良预后明显相关（

0.01）。

结论

METTL3介导的m

A修饰可能通过调节ABC转运蛋白、调节干细胞多能性的信号通路、TGF-β信号通路等经典耐药信号通路促进结直肠癌OXA耐药。

Abstract

Objective

To investigate the role of N

-methyladenosine （m

A） mediated by methyltransferase-like 3（METTL3） in oxaliplatin（OXA） resistance of colorectal cancer.

Methods

Concentration gradient induction method was used to establish OXA resistant cell line HCT116/OXA，and CCK-8 was used to detect the drug resistance of cells. Dot blot and ELISA were used to analyze the expression level of m

A in HCT116/OXA and parental cells. RNA-seq and qRT-PCR were used to screen the differential regulators of m

A. Western blot was used to detect the expression level of METTL3. METTL3 was overexpressed in HCT116 by adenovirus infection technique，and the proliferation activity of each group was detected by CCK-8. The key genes and signal pathways of m

A modification and regulation mediated by METTL3 related to drug resistance were screened through the combined analysis of MeRIP-seq and RNA-seq data of METTL3 knocked out by HCT116 cells in GEO database and RNA-seq data of drug-resistant cells. The correlation between METTL3 and prognosis was analyzed by TCGA database.

Results

The resistance of HCT116/OXA cells to OXA was significantly higher than that of their parents（

0.01）. Compared with HCT116 cells，the level of RNA m6A modification in HCT116/OXA cells was significantly up-regulated（

0.01） and the expression of METTL3 was significantly increased. Overexpression of METTL3 significantly enhanced the resistance of HCT116 cells to OXA（

0.01）. Differential genes selected from multiomics data conjoint analysis，related to drug resistance and regulated by METTL3-mediated m6A modification had significant correlation to ABC transporters，stem cell pluripote

ncy，TGF-β signaling pathway and other signaling pathways. The high expression of METTL3 was significantly correlated with the poor prognosis of colorectal cancer patients（

0.01）.

Conclusion

METTL3 mediated m

A methylation modification may promote the OXA resistance of colorectal cancer by regulating ABC transporter，stem cell pluripotency and TGF-β signaling pathway and other classical drug resistance signaling pathways.

关键词

Keywords

references

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Role of N6-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer

DOI：10.13406/j.cnki.cyxb.003077

摘要

Abstract

关键词

Keywords

references

Role of N⁶-methyladenosine mediated by methyltransferase-like 3 in oxaliplatin resistance of colorectal cancer