TIMP-2 Regulates 5-Fu Resistance via the ERK/MAPK Signaling Pathway in Colorectal Cancer

Background: 5-Fluorouracil (5-Fu) is the first-line chemotherapeutic drug in the treatment of colorectal cancer. The efficiency of 5-Fu is limited by drug resistance in colorectal cancer patients. This study was aimed to define the functions of tissue inhibitor metalloproteinases 2 (TIMP-2) in the 5-Fu resistance to colorectal cancer and investigate its potential mechanism.Methods: Cytokine array, ELISA and RT-qPCR were performed to detect cytokine expression levels. Western blot and immunohistochemistry were used to show the differential expression of proteins. In addition, cell viability was detected by CCK-8.Results: We established that there is an up-regulation in the expression of the TIMP-2 in colorectal cancer patients. This up-regulation in TIMP-2 expression was evident in 5-Fu resistant colorectal cancer patients and resulted in a poor prognosis. Besides, in vivo, clinical studies and patient-derived xenograft (PDX) models confirmed that TIMP-2 was highly expressed in the 5-Fu-resistant colorectal cancer. We deduced 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 via an autocrine mechanism. The 5-Fu resistance could overcome by the inhibition of TIMP-2 by anti-TIMP-2 antibody or ERK/MAPK by U0126.Conclusion: Our findings identify a TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism in colorectal cancer. Moreover, we recommend the use of an ERK/MAPK signal pathway inhibitor or TIMP-2-mediated immunotherapy for 5-Fu resistant colorectal cancer.