The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases

被引：116

作者：

Odagiri, Haruki ^{[1
,2
]}

Kadomatsu, Tsuyoshi ^{[1
]}

Endo, Motoyoshi ^{[1
]}

Masuda, Tetsuro ^{[1
,2
]}

Morioka, Masaki Suimye ^{[3
]}

Fukuhara, Shigetomo ^{[4
]}

Miyamoto, Takeshi ^{[5
]}

Kobayashi, Eisuke ^{[5
]}

Miyata, Keishi ^{[1
]}

Aoi, Jun ^{[1
]}

Horiguchi, Haruki ^{[1
]}

Nishimura, Naotaka ^{[1
]}

Terada, Kazutoyo ^{[1
]}

Yakushiji, Toshitake ^{[2
]}

Manabe, Ichiro ^{[3
]}

Mochizuki, Naoki ^{[4
]}

Mizuta, Hiroshi ^{[2
]}

Oike, Yuichi ^{[1
,6
]}

机构：

[1] Kumamoto Univ, Grad Sch Med Sci, Dept Med Genet, Chuo Ku, Kumamoto 8608556, Japan

[2] Kumamoto Univ, Grad Sch Med Sci, Dept Orthoped Surg, Kumamoto 8608556, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Bunkyo Ku, Tokyo 1138655, Japan

[4] Natl Cerebral & Cardiovasc Ctr, Res Inst, Dept Cell Biol, Suita, Osaka 5658565, Japan

[5] Keio Univ, Sch Med, Dept Orthoped Surg, Shinjuku Ku, Tokyo 1608582, Japan

[6] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Chiyoda Ku, Tokyo 1020075, Japan

来源：

SCIENCE SIGNALING | 2014年 / 7卷 / 309期

基金：

日本学术振兴会; 日本科学技术振兴机构;

关键词：

ANGIOPOIETIN-LIKE PROTEIN-2; TUMOR-SUPPRESSOR; GENE-EXPRESSION; MICROENVIRONMENTAL REGULATION; LUNG METASTASIS; CANCER; INFLAMMATION; ANGIOGENESIS; METABOLISM; JUNCTIONS;

D O I：

10.1126/scisignal.2004612

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The tumor microenvironment can enhance the invasive capacity of tumor cells. We showed that expression of angiopoietin-like protein 2 (ANGPTL2) in osteosarcoma (OS) cell lines increased and the methylation of its promoter decreased with time when grown as xenografts in mice compared with culture. Compared with cells grown in normal culture conditions, the expression of genes encoding DNA demethylation-related enzymes increased in tumor cells implanted into mice or grown in hypoxic, serum-starved culture conditions. ANGPTL2 expression in OS cell lines correlated with increased tumor metastasis and decreased animal survival by promoting tumor cell intravasation mediated by the integrin a5b1, p38 mitogen-activated protein kinase, and matrix metalloproteinases. The tolloid-like 1 (TLL1) protease cleaved ANGPTL2 into fragments in vitro that did not enhance tumor progression when overexpressed in xenografts. Expression of TLL1 was weak in OS patient tumors, suggesting that ANGPTL2 may not be efficiently cleaved upon secretion from OS cells. These findings demonstrate that preventing ANGPTL2 signaling stimulated by the tumor microenvironment could inhibit tumor cell migration and metastasis.

引用

页数：14

共 64 条

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Rap1 potentiates endothelial cell junctions by spatially controlling myosin II activity and actin organization [J].