title: Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer.
abstract: Overexpression of the HER2 oncogene contributes to tumor angiogenesis, which is an essential hallmark of cancer. Simvastatin has been reported to exhibit antitumor activities in several cancers; however, its roles and molecular mechanismsin the regulation of colorectal angiogenesis remain to be clarified. Here, we show that colon cancer cells express high levels of VEGF, total HER2 and phosphorylated HER2, and simvastatin apparently decreased their expression in HER2-overexpressing colon cancer cells. Simvastatin pretreatment reduced endothelial tube formation in vitro and microvessel density in vivo. Furthermore, simvastatin markedly inhibited tumor angiogenesis even in the presence of heregulin (HRG)-β1 (a HER2 co-activator) pretreatment in HER2+ tumor cells. Mechanistic investigation showed that simvastatin significantly abrogated HER2-induced tumor angiogenesis by inhibiting VEGF secretion. Together, these results provide a novel mechanism underlying the simvastatin-induced inhibition of tumor angiogenesis through regulating HER2/VEGF axis.
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of General Surgery, Shanghai Pudong New area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201200, China. Electronic address: wybpd@sina.com.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000068258:Bevacizumab / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D019821:Simvastatin; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C508053:ERBB2 protein, human
keywords: Anti-angiogenesis; Colorectal cancer; HER2; Simvastatin; VEGF