Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP-13 expression
Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP-13 expression
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他莫昔芬通过激活 MMP-2 和 MMP-13 表达诱导小鼠疝气的发生。
DOI：
10.1016/j.bbadis.2015.02.006
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发表时间：
2015-05-01
影响因子：
6.2
通讯作者：
Han, Jihong
中科院分区：
文献类型：
--
作者：
Ma, Xingzhe;Liu, Ying;Han, Jihong
疝是一种胶原蛋白合成/代谢缺陷的疾病。然而，疝形成的潜在机制尚未完全确定。他莫昔芬是一种选择性雌激素受体调节剂，用于乳腺癌患者。他莫昔芬也有多效性和副作用。在此，我们报告说，他莫昔芬治疗导致出现一个大的隆起，在下腹部之间的后腿在男性，但不是在女性小鼠。尸检表明，下腹壁破裂，大量肠从腹腔脱出。组织学分析表明，他莫昔芬引起下腹壁结构异常，这与II型胶原蛋白含量降低有关。此外，我们确定了组织中基质金属蛋白酶-2（MMP-2）和MMP-13的表达增加。在体外，他莫昔芬诱导MMP-2和MMP-13在成纤维细胞中的表达。启动子活性分析和ChIP试验表明，MMP-13表达的诱导与JNK-AP-1和ERK 1/2信号通路的激活有关，而MMP-2表达的诱导与ERK 1/2信号通路的激活有关。总之，我们的研究建立了一种新的鼠疝模型，定义了他莫昔芬的严重副作用，并建议对接受他莫昔芬治疗的男性患者给予警告（C）2015 Elsevier B. V.版权所有。
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 (C) 2015 Elsevier B.V. All rights reserved.