MMP12 knockout prevents weight and muscle loss in tumor-bearing mice

Abstract Background Colorectal 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,...

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Autores principales:	Lingbi Jiang, Mingming Yang, Shihui He, Zhengyang Li, Haobin Li, Ting Niu, Dehuan Xie, Yan Mei, Xiaodong He, Lili Wei, Pinzhu Huang, Mingzhe Huang, Rongxin Zhang, Lijing Wang, Jiangchao Li
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	MMP12 ApcMin/+ Macrophage IL-6 Cancer cachexia Colorectal cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/e41c65c1872c4d6c96f77bdd0e9d74f6
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spelling	oai:doaj.org-article:e41c65c1872c4d6c96f77bdd0e9d74f62021-12-05T12:19:29ZMMP12 knockout prevents weight and muscle loss in tumor-bearing mice10.1186/s12885-021-09004-y1471-2407https://doaj.org/article/e41c65c1872c4d6c96f77bdd0e9d74f62021-12-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-09004-yhttps://doaj.org/toc/1471-2407Abstract Background Colorectal 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. Methods ApcMin/+; 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. Results MMP12 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. Conclusions MMP12 is essential for controlling body weight of Apc Min/+ 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.Lingbi JiangMingming YangShihui HeZhengyang LiHaobin LiTing NiuDehuan XieYan MeiXiaodong HeLili WeiPinzhu HuangMingzhe HuangRongxin ZhangLijing WangJiangchao LiBMCarticleMMP12ApcMin/+MacrophageIL-6Cancer cachexiaColorectal cancerNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MMP12 ApcMin/+ Macrophage IL-6 Cancer cachexia Colorectal cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	MMP12 ApcMin/+ Macrophage IL-6 Cancer cachexia Colorectal cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lingbi Jiang Mingming Yang Shihui He Zhengyang Li Haobin Li Ting Niu Dehuan Xie Yan Mei Xiaodong He Lili Wei Pinzhu Huang Mingzhe Huang Rongxin Zhang Lijing Wang Jiangchao Li MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
description	Abstract Background Colorectal 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. Methods ApcMin/+; 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. Results MMP12 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. Conclusions MMP12 is essential for controlling body weight of Apc Min/+ 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.
format	article
author	Lingbi Jiang Mingming Yang Shihui He Zhengyang Li Haobin Li Ting Niu Dehuan Xie Yan Mei Xiaodong He Lili Wei Pinzhu Huang Mingzhe Huang Rongxin Zhang Lijing Wang Jiangchao Li
author_facet	Lingbi Jiang Mingming Yang Shihui He Zhengyang Li Haobin Li Ting Niu Dehuan Xie Yan Mei Xiaodong He Lili Wei Pinzhu Huang Mingzhe Huang Rongxin Zhang Lijing Wang Jiangchao Li
author_sort	Lingbi Jiang
title	MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
title_short	MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
title_full	MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
title_fullStr	MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
title_full_unstemmed	MMP12 knockout prevents weight and muscle loss in tumor-bearing mice
title_sort	mmp12 knockout prevents weight and muscle loss in tumor-bearing mice
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e41c65c1872c4d6c96f77bdd0e9d74f6
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MMP12 knockout prevents weight and muscle loss in tumor-bearing mice

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