MMP12 knockout prevents weight and muscle loss in tumor-bearing mice.
MMP12 knockout prevents weight and muscle loss in tumor-bearing mice.
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MMP12 敲除可防止荷瘤小鼠体重和肌肉损失
DOI：
10.1186/s12885-021-09004-y
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发表时间：
2021-12-04
期刊：
影响因子：
3.8
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Jiang L;Yang M;He S;Li Z;Li H;Niu T;Xie D;Mei Y;He X;Wei L;Huang P;Huang M;Zhang R;Wang L;Li J
结直肠癌是一种恶性消化道肿瘤，部分晚期患者可发生癌性恶病质（CAC）。CAC被定义为一种多因素综合征，其特征在于体重减轻和肌肉减少（有或没有脂肪量），导致进行性功能障碍，从而增加发病率和死亡率。ApcMin/+小鼠发生自发性肠腺瘤，为CAC研究提供了建立的结直肠癌模型。在研究ApcMin/+小鼠模型时，我们观察到大约从第15周开始体重增加显著减少。当ApcMin/+小鼠与MMP 12 −/−小鼠杂交时，体重增加的减少得到了挽救，这表明MMP 12在与年龄相关的ApcMin/+相关的体重减轻中起作用。作为对照，MMP 12 −/−小鼠的体重在每周的基础上，它们的体重与WT mice.MethodsApcMin/+; MMP 12 −/−小鼠通过将ApcMin/+小鼠与MMP 12敲除（MMP 12 −/−）小鼠杂交获得。使用苏木精-伊红（H&E）染色评估组织学评分。MMP 12的表达通过免疫组织化学和免疫荧光染色证实。采用ELISA、蛋白质芯片和定量聚合酶链反应（qPCR）检测肿瘤是否上调IL-6。采用细胞分析和蛋白质印迹法验证IL-6与MMP 12之间的调节关系。测量荧光强度以确定MMP 12是否与胰岛素和胰岛素样生长因子1（IGF-1）在体外相关。结果MMP 12基因敲除可导致ApcMin/+小鼠体重增加，肌纤维横截面积增大（所有小鼠均为C57 BL/6背景），而抑制MMP 12可抑制ApcMin/+小鼠体重下降。MMP 12在ApcMin/+小鼠的肌肉组织和腹腔巨噬细胞中表达上调。IL-6在肿瘤细胞和结直肠癌患者中呈上调。结论MMP 12对ApcMin/+小鼠的体重控制起重要作用。我们的研究表明，在肌肉组织中，肿瘤细胞分泌IL-6诱导巨噬细胞上调MMP-12，这是肿瘤细胞与巨噬细胞之间的相互作用。本研究为MMP 12治疗CAC所致体重减轻提供了新的视角。
BackgroundColorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+mice were crossed with MMP12−/−mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12−/−mice on a weekly basis, their weight were not significantly different from those of WT mice.MethodsApcMin/+; MMP12−/−mice were obtained by crossing ApcMin/+mice with MMP12 knockout (MMP12−/−) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+mice.ResultsMMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage.ConclusionsMMP12 is essential for controlling body weight of ApcMin/+mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.
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影响因子：
5.6
作者：
Kasprzak A
通讯作者：
Kasprzak A
DOI：
10.1016/j.bbagen.2012.12.024
发表时间：
2013-04-01
影响因子：
3
作者：
Bauters, D.;Van Hul, M.;Lijnen, H. R.
通讯作者：
Lijnen, H. R.
影响因子：
5.7
作者：
Amor, Melina;Moreno-Viedma, Veronica;Stulnig, Thomas M.
通讯作者：
Stulnig, Thomas M.
影响因子：
64.5
作者：
Hotary, KB;Allen, ED;Weiss, SJ
通讯作者：
Weiss, SJ
影响因子：
7.3
作者：
Li, Wei;Li, Jianchang;Mansour, Tarek S.
通讯作者：
Mansour, Tarek S.