Abstract
Purpose
This study aims to evaluate the value of tissue inhibitors of MMPs-2 (TIMP-2) to indicate 5-Fluorouracil (5-Fu) resistance status in colorectal cancer.
Methods
The 5-Fu resistance of colorectal cancer cell lines was detected using Cell-Counting Kit-8 (CCK-8) and calculated using IC50. Enzyme-linked immunosorbent assay (ELISA) and real time-quantitative polymerase chain reaction (RT-qPCR) were used to detect TIMP-2 expression level in the culture supernatant and serum. Twenty-two colorectal cancer patients' TIMP-2 levels and clinical characteristics were analyzed before and after chemotherapy. Additionally, the patient-derived xenograft (PDX) model of 5-Fu resistance was used to evaluate the feasibility of TIMP-2 as a predictive biomarker of 5-Fu resistance.
Results
Our experimental results display that TIMP-2 expression is elevated in colorectal cancer drug-resistant cell lines, and its expression level is closely related to 5-Fu resistance. Moreover, TIMP-2 in colorectal cancer patient serum undergoing 5-Fu-based chemotherapy could indicate their drug resistance status, and its efficacy is higher than CEA and CA19-9. Finally, PDX model animal experiments reveal that TIMP-2 can detect 5-Fu resistance in colorectal cancer earlier than tumor volume.
Conclusion
TIMP-2 is a good indicator of 5-Fu resistance in colorectal cancer. Monitoring the serum TIMP-2 level can help the clinician identify 5-Fu resistance in colorectal cancer patients earlier during chemotherapy.
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Data availability
Data supporting the findings of this study are available from the Department of Gastrointestinal Surgery, Shaoxing People's Hospital, but the availability of these data is limited; they are used under the license of the current study and are, therefore, unavailable publicly available. Data are available from the authors upon reasonable request and with permission of the Department of Gastrointestinal Surgery, Shaoxing People's Hospital.
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Funding
This work was supported by Zhejiang Province Health Science and Technology Plan, China (Grant Numbers: 2023KY1234, 2021RC133, and 2021KY1150), Shaoxing Health Science and Technology Program, Zhejiang Province, China (Grant Number: 2022SY014), and Shaoxing Bureau of Science and Technology, Zhejiang Province, China (Grant Number: 2020A13022).
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YL and LS: performed the experiments, writing—original draft, and wrote the manuscript. CX and RZ: performed the experiments. GH and KT: formal analysis, analyzed the data, and conducted the experiments. GZ, FT, and ZL: supervised the study.
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The human and animal ethics involved in this experiment were approved by the ethical approval agency at Shaoxing People's Hospital. Study number: 2021-K-Y-158-01.
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Li, Y., Xu, C., Zhu, R. et al. TIMP-2 as a predictive biomarker in 5-Fu-resistant colorectal cancer. J Cancer Res Clin Oncol 149, 7235–7246 (2023). https://doi.org/10.1007/s00432-023-04670-w
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DOI: https://doi.org/10.1007/s00432-023-04670-w