Vastatin is an Endogenous Antiangiogenesis Polypeptide Lost in Hepatocellular Carcinoma and Effectively Inhibits Tumor Metastasis
Vastatin is an Endogenous Antiangiogenesis Polypeptide Lost in Hepatocellular Carcinoma and Effectively Inhibits Tumor Metastasis
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伐他汀是一种在肝细胞癌中丢失的内源性抗血管生成多肽，可有效抑制肿瘤转移
DOI：
10.1038/mt.2016.56
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发表时间：
2016
影响因子：
12.4
通讯作者：
Lin Marie Chia-mi
中科院分区：
文献类型：
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作者：
Shen Zan;Yao Chen;Wang Zifeng;Yue Lu;Fang Zheping;Yao Hong;Lin Feng;Zhao Hui;Sun Yuan-Jue;Bian Xiu-wu;Wang Xiaomei;Li Yi;Lu Gang;Poon Wai Sang;Kung Hsiang-Fu;Lin Marie Chia-mi
肝细胞癌（HCC）是一种缺乏有效治疗的富血管性癌症。Vastatin是一种内源性多肽，在正常肝组织中表达，但在大多数肝癌患者（73.1%）的肝脏中丢失。其表达水平与肝癌患者肿瘤大小（P =0.035）和转移（P= 0.016）呈负相关。为了评估其作为治疗剂的潜在用途，我们构建了携带Vastatin的重组腺相关病毒（rAAV-Vastatin）来治疗原位布法罗大鼠模型中的HCC。rAAV-Vastatin治疗显著延长了中位生存期，抑制了肿瘤生长，并通过降低微血管密度和增加肿瘤坏死来完全预防肝癌转移。在非荷瘤小鼠中未观察到可检测的毒性。为了研究其分子机制，我们进行了DNA微阵列，蛋白质印迹分析和生物信息学分析，以确定其对全球基因表达模式和信号转导途径的影响。我们的结果表明，rAAV-Vastatin显著降低Pck 1，JAG 2和c-Fos的表达，从而分别抑制细胞代谢，Notch和AP-1信号通路。因此，我们首次证明Vastatin是一种新型、安全、有效的抗血管生成治疗药物，也是HCC的潜在生物标志物。
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.