Mechanism of TOM1L1 inducing overexpression of MMPs through up-regulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway to promote CRC invasion and metastasis

Hu Xiaofeng; Liu Bin; Wang Yifei; Wang Feng; Nie Shuangfa; Wu Xueliang

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Mechanism of TOM1L1 inducing overexpression of MMPs through up-regulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway to promote CRC invasion and metastasis

更新时间：2026-07-01

- Mechanism of TOM1L1 inducing overexpression of MMPs through up-regulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway to promote CRC invasion and metastasis
- Journal of Chongqing Medical University Pages: 1-12(2026)
- 作者机构：
  
  1.河北北方学院附属第一医院普外二科，张家口 075000
  2.河北北方学院附属第一医院普外一科，张家口 075000
- 作者简介：
- 基金信息：
- DOI：
  CLC： R735.34
- Received：26 March 2025，
  
  Published：01 July 2026
- 稿件说明：
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Hu Xiaofeng,Liu Bin,Wang Yifei,et al.Mechanism of TOM1L1 inducing overexpression of MMPs through up-regulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway to promote CRC invasion and metastasis[J].Journal of Chongqing Medical University,
DOI：

Hu Xiaofeng,Liu Bin,Wang Yifei,et al.Mechanism of TOM1L1 inducing overexpression of MMPs through up-regulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway to promote CRC invasion and metastasis[J].Journal of Chongqing Medical University, DOI：10.13406/j.cnki.cyxb..

摘要

目的

探讨TOM1样蛋白1（target of myb 1 like protein 1，TOM1L1）通过上调核因子E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）/十-十一易位甲基胞嘧啶双加氧酶3（ten-eleven translocation methylcytosine dioxygenase 3，TET3）/含Src同源2结构域蛋白酪氨酸磷酸酶2（Src homology 2 domain-containing protein tyrosine phosphatase 2，SHP2）/细胞外信号调节激酶1/2（extracellular signal-regulated kinase 1/2，ERK1/2）信号通路促进基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达，进而促进结直肠癌（colorectal cancer，CRC）侵袭转移的机制。

方法

通过生物信息学分析发现TOM1L1在CRC组织中显著高表达，并构建小鼠模型进行免疫组化染色。采用蛋白质印迹法（Western blot）、免疫共沉淀（co-immunoprecipitation，Co-IP）和实时荧光定量聚合酶链反应（real-time quantitative polymerase chain reaction，qPCR）检测信号通路关键蛋白及MMPs的表达水平。通过划痕实验和Transwell实验分析细胞迁移和侵袭能力，并采用抑制剂（PHPS1、SCH772984）阻断SHP2和ERK1/2活性以验证反馈调控机制。

结果

研究显示，TOM1L1过表达显著上调MMP2/MMP9表达水平，并与磷酸化SHP2（phosphorylated SHP2，p-SHP2）、磷酸化ERK1/2（phosphorylated ERK1/2，p-ERK1/2）形成正反馈循环。此外，抑制p-SHP2和ERK1/2的活性可降低TOM1L1表达，表明三者间存在相互促进关系。实验验证了TOM1L1通过该信号通路正反馈机制加速CRC的侵袭和转移。

结论

本研究揭示了TOM1L1通过多重信号通路的正反馈机制，显著促进了CRC的侵袭和转移，提示TOM1L1可能成为潜在的治疗靶点。这一发现为CRC的早期诊断和治疗提供了新视角和新策略。

Abstract

Objective

This study aims to investigate the mechanism by which TOM1L1 promotes the expression of matrix metalloproteinases（MMPs） through the upregulation of the Nrf2/TET3/SHP2/ERK1/2 signaling pathway，thereby facilitating the invasion and metastasis of colorectal cancer （CRC）.

Methods

Through bioinformatics analysis，it was found that TOM1L1 was significantly highly expressed in CRC tissues，and a mouse model was constructed for immunohistochemical staining experiments. Western blot，co-immunoprecipitation（Co-IP） experiments，and q-PCR experiments were used to detect the expression levels of key proteins in the signaling pathway and MMPs. The cell migration and invasion abilities were analyzed by scratch test and Transwell assay，and inhibitors （PHPS1，SCH772984） were used to block the activities of SHP2 and ERK1/2 to verify the feedback regulation mechanism.

Results

The results demonstrated that TOM1L1 overexpression significantly upregulated the expression levels of MMP2/MMP9 and formed a positive feedback loop with p-SHP2 and p-ERK1/2. Additionally，inhibition of p-SHP2 and ERK1/2 activity led to reduced TOM1L1 expression，indicating a mutually reinforcing relationship among the three. The experiments confirmed that TOM1L1 accelerates CRC invasion and metastasis through this positive feedback mechanism of the signaling pathway.

Conclusion

This study reveals that TOM1L1 significantly promotes CRC invasion and metastasis through a multi-signaling pathway positive feedback mechanism，suggesting that TOM1L1 may serve as a potential therapeutic target. This discovery provides new perspectives and strategies for the early diagnosis and treatment of CRC.

关键词

Keywords

references

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