Vastatin is an Endogenous Antiangiogenesis Polypeptide Lost in Hepatocellular Carcinoma and Effectively Inhibits Tumor Metastasis

摘要

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 microvessel density (P = 0.020), 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 non-tumor-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 genes involved in the cellular metabolism, Notch signaling, and AP-1 signaling pathways, respectively. Taken together, we demonstrated for the first time that vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC.