Carcinogenesis Advance Access originally published online on February 10, 2006
Carcinogenesis 2006 27(5):1113-1120; doi:10.1093/carcin/bgi351
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Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma
1 Division of Medical Oncology, Department of Medicine. 2 Division of Colorectal Surgery, Department of Surgery, 3 Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China, 4 National Yang-Ming University School of Medicine and 5 Institute of Biopharmaceutical Science, College of Life Science, National Yang-Ming University, Taipei, Taiwan, Republic of China
* To whom correspondence should be addressed. Tel: +886 2 2826 7143; Fax: +886 2 2825 0883; Email: yeusu{at}ym.edu.tw
The ability of tumor cells to resist apoptosis triggered by immune cells results in their escape from immune surveillance of the host. A critical effector of apoptosis is the Fas/Fas ligand (FasL) system that mediates the tumoricidal effects of cytotoxic T cells. Recently, in vitro cleavage of Fas expressed in various tumor cells by matrix metalloproteinase-7 (MMP-7) was demonstrated. In the present study, we first analyzed the influence of this metalloproteinase on Fas signaling in SW480, HCT-15 and HT-29 colorectal carcinoma (CRC) cells by assessing their responses to either an agonistic Fas antibody (CH11) or the FasL-bearing Jurkat cells after they were pretreated with MMP-7. Interestingly, both antibody- and Jurkat cell-induced apoptosis in three different CRC lines were significantly reduced by MMP-7 pretreatment. Additionally, immunohistochemical (IHC) staining was used to examine the expression levels of MMP-7 and Fas in tumor samples of 54 CRC patients. In agreement with our in vitro observation, the expression of MMP-7 in tumor tissues was inversely correlated with those of Fas (P < 0.001; 
2-test). Moreover, shortened survival was found in patients with a higher MMP-7 and a lower Fas expression, respectively, in their tumor tissues (P < 0.0001). Finally, by multivariate analysis, we discovered that MMP-7 (P = 0.001) and Fas levels (P = 0.036) were independent prognostic factors for CRC patients. These results suggest that Fas downregulation and a consequential increased resistance to FasL-triggered apoptosis resulting from upregulated MMP-7 in colorectal cancer cells could be a key mechanism for their escape from the immune surveillance, thereby predicting a poor survival in CRC patients.
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