title: Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis.
abstract: Hepatocellular carcinoma (HCC) is a hypervascular cancer without effective treatment. Here we report that polypeptide of NC1 domain of type VIII collagen (Vastatin) is an endogenous polypeptide expressed in normal liver tissue but lost in the liver of most HCC patients (73.1%). Its expression level is negatively associated with tumor size (P = 0.035) and metastasis (P = 0.016) in HCC patients. To evaluate its potential use as a therapeutic, we constructed a recombinant adeno-associated virus carrying Vastatin (rAAV-Vastatin) to treat HCC in an orthotopic Buffalo rat model. rAAV-Vastatin treatment significantly prolonged the median survival, inhibited tumor growth, and completely prevented metastasis in HCC-bearing rats by decreasing microvessel density and increasing tumor necrosis. No detectable toxicity in nontumor-bearing mice was observed. To investigate its molecular mechanisms, we performed DNA microarray, western blotting assays, and bioinformatic analysis to determine its effect on global gene expression patterns and signal transduction pathways. Our results indicated that rAAV-Vastatin significantly reduced the expressions of Pck1, JAG2, and c-Fos, thus inhibiting the cellular metabolism, Notch and AP-1 signaling pathways, respectively. Hence, we demonstrated for the first time that Vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC.
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Orthopaedics, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Shenzhen Key Lab of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.|Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Zifeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Hepatobiliary Surgery, Taizhou Hospital, Wenzhou Medical University, Zhejiang, China.
authors.forename: Zheping
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Jiangsu Eng. Lab of Cancer Biotherapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yuan-Jue
authors.initials: YJ
authors.lastname: Sun
authors.affiliation: Institute of Pathology, Southwest Cancer Center, Chongqing, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Shenzhen Key Lab of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Shenzhen Key Lab of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.affiliation: Institute of Pathology, Southwest Cancer Center, Chongqing, China.
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.affiliation: Shenzhen Key Lab of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Marie Chia-Mi
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D024102:Collagen Type VIII / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014161:Transduction, Genetic; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D024102:Collagen Type VIII; D051880:Receptors, Notch; D018808:Transcription Factor AP-1; C441971:vastatin