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Research Paper|Volume 14, Issue 1|pp 297—315

TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer

Guolin Zhang1,2, Xin Luo1, Zian Wang1,3, Jianbin Xu4, Wei Zhang1, Engeng Chen1, Qing Meng1, Di Wang1, Xuefeng Huang1, Wei Zhou1, Zhangfa Song1
  • 1Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
  • 2Department of Gastrointestinal Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang Province, China
  • 3Department of Colorectal Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang Province, China
  • 4Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
* Equal contribution as co-first authors
Received: July 1, 2021Accepted: December 3, 2021Published: January 12, 2022
https://doi.org/10.18632/aging.203793

Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

5-Fluorouracil (5-Fu) is the first-line chemotherapeutic option for colorectal cancer. However, its efficacy is inhibited by drug resistance. Cytokines play an important role in tumor drug resistance, even though their mechanisms are largely unknown. Using a cytokine array, we established that tissue inhibitor metalloproteinase 2 (TIMP-2) is highly expressed in 5-Fu resistant colorectal cancer patients. Analysis of samples from 84 patients showed that elevated TIMP-2 expression levels in colorectal patients were correlated with poor prognostic outcomes. In a 5-Fu-resistant patient-derived xenograft (PDX) model, TIMP-2 was also found to be highly expressed. We established an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway. Inhibition of TIMP-2 using an anti-TIMP-2 antibody or ERK/MAPK inhibition by U0126 suppressed TIMP-2 mediated 5-Fu-resistance in CRC patients. In conclusion, a novel TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism is involved in colorectal cancer. Therefore, targeting TIMP-2 or ERK/MAPK may provide a new strategy to overcome 5-Fu resistance in colorectal cancer chemotherapy.