title: Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP-13 expression.
abstract: Hernia is a disease with defects in collagen synthesis/metabolism. However, the underlying mechanisms for hernia formation have not been fully defined. Tamoxifen is a selective estrogen receptor modulator and used for patients with breast cancer. Tamoxifen also has pleiotropic and side effects. Herein, we report that tamoxifen treatment resulted in an appearance of a large bulge in the low abdomen between the hind legs in male but not in female mice. The autopsy demonstrated that the low abdominal wall was broken and a large amount of intestine herniated out of the abdominal cavity. Histological analysis indicated that tamoxifen caused structural abnormalities in the low abdominal wall which were associated with decreased type II collagen content. Furthermore, we determined increased matrix metalloproteinase-2 (MMP-2) and MMP-13 expression in the tissue. In vitro, tamoxifen induced MMP-2 and MMP-13 expression in fibroblasts. The promoter activity analysis and ChIP assay demonstrate that induction of MMP-13 expression was associated with activation of JNK-AP-1 and ERK1/2 signaling pathways while induction of MMP-2 expression was related to activation of the ERK1/2 signaling pathway. Taken together, our study establishes a novel murine hernia model, defines a severe side effect of tamoxifen, and suggests a caution to male patients receiving tamoxifen treatment.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xingzhe
authors.initials: X
authors.lastname: Ma
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Qixue
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Medicine, Nankai University, Tianjin, China.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Medicine, Nankai University, Tianjin, China; Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Life Sciences, Nankai University, Tianjin, China. Electronic address: yajunduan@nankai.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Life Sciences, Nankai University, Tianjin, China; Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. Electronic address: jihonghan2008@nankai.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
mesh_terms: D034861:Abdominal Wall / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D024043:Collagen Type II / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006547:Hernia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000633:toxicity; D012737:Sex Factors; D013629:Tamoxifen / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2
keywords: AP-1; Collagen; Fibroblast; Hernia; MMP-13; Tamoxifen