TIMP‐2 Modulates 5‐Fu Resistance in Colorectal Cancer Through Regulating JAK–STAT Signalling Pathway
ABSTRACT The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal...
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| Published in | Journal of cellular and molecular medicine Vol. 29; no. 6; pp. e70470 - n/a |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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John Wiley & Sons, Inc
01.03.2025
John Wiley and Sons Inc |
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| Abstract | ABSTRACT
The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC. |
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| AbstractList | ABSTRACT
The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC. The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK-STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK-STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC. The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC 50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC. The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC 50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC. The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK-STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC. ABSTRACT The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC. |
| Author | Zhang, Guolin Xu, Chuchu Xu, Guangen Li, Yaoqing Hu, Gengyuan Dai, Qingfeng Xu, Yuhong Zhu, Renjun Tao, Kelong |
| AuthorAffiliation | 3 Zhijiang College, Zhejiang University of Technolog Shaoxing Zhejiang Province China 1 Department of Gastrointestinal Surgery Shaoxing People's Hospital Shaoxing Zhejiang Province China 2 Department of Emergency Shaoxing People's Hospital Shaoxing Zhejiang Province China 4 Department of Gynaecology Shaoxing People's Hospital Shaoxing Zhejiang Province China |
| AuthorAffiliation_xml | – name: 4 Department of Gynaecology Shaoxing People's Hospital Shaoxing Zhejiang Province China – name: 3 Zhijiang College, Zhejiang University of Technolog Shaoxing Zhejiang Province China – name: 1 Department of Gastrointestinal Surgery Shaoxing People's Hospital Shaoxing Zhejiang Province China – name: 2 Department of Emergency Shaoxing People's Hospital Shaoxing Zhejiang Province China |
| Author_xml | – sequence: 1 givenname: Chuchu surname: Xu fullname: Xu, Chuchu organization: Shaoxing People's Hospital – sequence: 2 givenname: Renjun surname: Zhu fullname: Zhu, Renjun organization: Shaoxing People's Hospital – sequence: 3 givenname: Qingfeng surname: Dai fullname: Dai, Qingfeng organization: Zhijiang College, Zhejiang University of Technolog – sequence: 4 givenname: Yaoqing surname: Li fullname: Li, Yaoqing organization: Shaoxing People's Hospital – sequence: 5 givenname: Gengyuan surname: Hu fullname: Hu, Gengyuan organization: Shaoxing People's Hospital – sequence: 6 givenname: Kelong surname: Tao fullname: Tao, Kelong organization: Shaoxing People's Hospital – sequence: 7 givenname: Yuhong surname: Xu fullname: Xu, Yuhong organization: Shaoxing People's Hospital – sequence: 8 givenname: Guangen surname: Xu fullname: Xu, Guangen organization: Shaoxing People's Hospital – sequence: 9 givenname: Guolin orcidid: 0000-0002-5836-4478 surname: Zhang fullname: Zhang, Guolin email: zhangguolin@zju.edu.cn organization: Shaoxing People's Hospital |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40118773$$D View this record in MEDLINE/PubMed |
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| Copyright | 2025 The Author(s). published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| DOI | 10.1111/jcmm.70470 |
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| Keywords | JAK–STAT signalling pathway TIMP‐2 5‐Fu colorectal cancer drug resistance |
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| License | Attribution 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
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| Notes | Funding This work was supported by the Medical Science and Technology Project of Zhejiang Province, China (Grant 2023KY1234, 2023KY1250), the Shaoxing Health Science and Technology Plan, Zhejiang Province, China (Grant 2024 SKY040) and the Shaoxing Bureau of Science and Technology, Zhejiang Province, China (Grant 2022SY014, 2023A14006). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Funding: This work was supported by the Medical Science and Technology Project of Zhejiang Province, China (Grant 2023KY1234, 2023KY1250), the Shaoxing Health Science and Technology Plan, Zhejiang Province, China (Grant 2024 SKY040) and the Shaoxing Bureau of Science and Technology, Zhejiang Province, China (Grant 2022SY014, 2023A14006). |
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| Snippet | ABSTRACT
The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients,... The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients,... The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients,... ABSTRACT The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients,... |
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| SubjectTerms | 5-Fluorouracil 5‐Fu Antibodies Cancer Cancer therapies Cell culture Cell cycle Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Chemotherapy Cholecystokinin Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Cytokines DNA methylation Drug delivery drug resistance Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Enzyme-linked immunosorbent assay Enzymes Fluorouracil - pharmacology Gene Expression Regulation, Neoplastic - drug effects Growth factors Humans JAK–STAT signalling pathway Janus Kinases - metabolism Kinases Male Medical prognosis Medical research Metastasis Molecules Original Ovaries Patients Proteins Signal transduction Signal Transduction - drug effects STAT Transcription Factors - metabolism TIMP‐2 Tissue Inhibitor of Metalloproteinase-2 - blood Tissue Inhibitor of Metalloproteinase-2 - genetics Tissue Inhibitor of Metalloproteinase-2 - metabolism Tissue inhibitor of metalloproteinases Western blotting |
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| Title | TIMP‐2 Modulates 5‐Fu Resistance in Colorectal Cancer Through Regulating JAK–STAT Signalling Pathway |
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