ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model
ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model
复制标题
DOI：
10.1002/path.4024
复制
发表时间：
2012-07-01
影响因子：
7.3
通讯作者：
Kemp, Christopher J.
中科院分区：
文献类型：
--
作者：
Busch, Stephanie E.;Gurley, Kay E.;Kemp, Christopher J.
肝脏血管肉瘤是一种致命的恶性肿瘤，其病因仍知之甚少。CDKN 2A基因座（包含ARF和p16（INK 4a）肿瘤抑制基因）的失活是血管肉瘤患者的常见事件，但ARF在血管肿瘤发生中的确切作用尚不清楚。为了确定ARF抑制血管瘤形成的程度，我们检查了暴露于致癌物尿烷[腹腔内（i. p.），1 mg/g]。Arf缺失导致发病率升高，并增加血管瘤和早期血管瘤的发病率。ARF对血管病变发展的抑制在很大程度上依赖于Arf基因剂量和小鼠的遗传品系。Trp 53缺陷小鼠暴露于氨基甲酸乙酯后也出现肝血管病变，表明ARF信号通过p53依赖性途径抑制肝血管肉瘤的发展。我们的研究结果提供了强有力的证据表明，失活的Arf是一个致病事件在血管瘤，并建议ARF途径可能是一个新的分子靶点，血管肉瘤患者的治疗干预。版权所有（c）2012大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Hepatic haemangiosarcoma is a deadly malignancy whose aetiology remains poorly understood. Inactivation of the CDKN2A locus, which houses the ARF and p16(INK4a) tumour suppressor genes, is a common event in haemangiosarcoma patients, but the precise role of ARF in vascular tumourigenesis is unknown. To determine the extent to which ARF suppresses vascular neoplasia, we examined the incidence of hepatic vascular lesions in Arf-deficient mice exposed to the carcinogen urethane [intraperitoneal (i.p.), 1 mg/g]. Loss of Arf resulted in elevated morbidity and increased the incidence of both haemangiomas and incipient haemangiosarcomas. Suppression of vascular lesion development by ARF was heavily dependent on both Arf gene-dosage and the genetic strain of the mouse. Trp53-deficient mice also developed hepatic vascular lesions after exposure to urethane, suggesting that ARF signals through a p53-dependent pathway to inhibit the development of hepatic haemangiosarcoma. Our findings provide strong evidence that inactivation of Arf is a causative event in vascular neoplasia and suggest that the ARF pathway may be a novel molecular target for therapeutic intervention in haemangiosarcoma patients. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.