Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer.
Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer.
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DOI：
10.1038/onc.2011.498
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发表时间：
2012-06-28
期刊：
影响因子：
8
通讯作者：
Chiba, T.
中科院分区：
文献类型：
--
作者：
Kawada, M.;Seno, H.;Kanda, K.;Nakanishi, Y.;Akitake, R.;Komekado, H.;Kawada, K.;Sakai, Y.;Mizoguchi, E.;Chiba, T.
几丁质酶 3 样 1 (CHI3L1) 是几丁质酶家族的哺乳动物成员之一，在多种类型的人类癌症中表达，CHI3L1 血清水平升高被认为是晚期癌症患者预后不良的生物标志物。然而，CHI3L1 在人类癌症中的总体生物学功能仍然未知。利用人类结直肠癌样本和人类细胞系进行研究，以表征 CHI3L1 在癌症病理生理学中的作用。结直肠癌中 CHI3L1 的血浆蛋白和组织 mRNA 表达水平强烈上调。免疫组织化学分析显示，CHI3L1在癌细胞中表达，且CHI3L1表达与浸润的巨噬细胞数量和微血管密度显着相关。通过跨孔迁移和管形成实验，SW480细胞（人结肠癌细胞）中CHI3L1的过度表达增强了THP-1细胞（人巨噬细胞）和HUVEC（人内皮细胞）的迁移以及HUVEC的管形成。通过RNA干扰敲低CHI3L1或通过抗CHI3L1抗体中和CHI3L1显示出对CHI3L1诱导的迁移和管形成的强烈抑制。细胞增殖实验显示CHI3L1过表达显着增强SW480细胞的增殖。 ELISA 分析显示，CHI3L1 通过丝裂原激活蛋白激酶 (MAPK) 信号通路增加 SW480 细胞炎症趋化因子 IL-8 和 MCP-1 的分泌。 SW480细胞中IL-8或MCP-1的中和以及MAPK的抑制或敲低均显着抑制CHI3L1诱导的迁移和管形成。在异种移植小鼠模型中，HCT116 细胞（人结肠癌细胞）中 CHI3L1 的过度表达增强了肿瘤生长以及巨噬细胞浸润和微血管密度。总之，结肠癌细胞中表达的 CHI3L1 促进癌细胞增殖、巨噬细胞募集和血管生成。因此，抑制CHI3L1活性可能是人类结直肠癌的一种新的治疗策略。
Chitinase 3-like 1 (CHI3L1), one of mammalian members of the chitinase family, is expressed in several types of human cancer, and elevated serum level of CHI3L1 is suggested to be a biomarker of poor prognosis in advanced cancer patients. However, the overall biological function of CHI3L1 in human cancers still remains unknown. Studies were performed to characterize the role of CHI3L1 in cancer pathophysiology utilizing human colorectal cancer samples and human cell lines. Plasma protein and tissue mRNA expression levels of CHI3L1 in colorectal cancer were strongly upregulated. Immunohistochemical analysis showed that CHI3L1 was expressed in cancer cells and CHI3L1 expression had a significant association with the number of infiltrated macrophages and microvessel density. By utilizing trans-well migration and tube formation assays, overexpression of CHI3L1 in SW480 cells (human colon cancer cells) enhanced the migration of THP-1 cells (human macrophage cells) and HUVECs (human endothelial cells), and the tube formation of HUVECs. The knockdown of CHI3L1 by RNA interference or the neutralization of CHI3L1 by anti-CHI3L1 antibody displayed strong suppression of CHI3L1-induced migration and tube formation. Cell proliferation assay showed that CHI3L1 overexpression significantly enhanced the proliferation of SW480 cells. ELISA analysis showed that CHI3L1 increased the secretion of inflammatory chemokines, IL-8 and MCP-1, from SW480 cells through mitogen-activated protein kinase (MAPK) signaling pathway. Both neutralization of IL-8 or MCP-1 and inhibition or knockdown of MAPK in SW480 cells significantly inhibited CHI3L1-induced migration and tube formation. In a xenograft mouse model, overexpression of CHI3L1 in HCT116 cells (human colon cancer cells) enhanced the tumor growth as well as macrophage infiltration and microvessel density. In conclusion, CHI3L1 expressed in colon cancer cells promotes cancer cell proliferation, macrophage recruitment and angiogenesis. Thus, the inhibition of CHI3L1 activity may be a novel therapeutic strategy for human colorectal cancer.
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影响因子：
5.3
作者：
Kawada, Kenji;Upadhyay, Geeta;Yajnik, Vijay
通讯作者：
Yajnik, Vijay
影响因子：
2
作者：
Kawada, Mayumi;Hachiya, Yuriko;Mizoguchi, Emiko
通讯作者：
Mizoguchi, Emiko
影响因子：
4.1
作者：
Ling, H;Recklies, AD
通讯作者：
Recklies, AD
影响因子：
158.5
作者：
Chupp, Geoffrey L.;Lee, Chun Geun;Elias, Jack A.
通讯作者：
Elias, Jack A.
影响因子：
6
作者：
Chen, Chun-Chuan;Pekow, Joel;Mizoguchi, Emiko
通讯作者：
Mizoguchi, Emiko