c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF.
c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF.
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DOI：
10.1016/j.jhep.2011.02.036
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发表时间：
2011-12
影响因子：
25.7
通讯作者：
Sarkar, Devanand
中科院分区：
文献类型：
--
作者：
Yoo, Byoung Kwon;Gredler, Rachel;Chen, Dong;Santhekadur, Prasanna K.;Fisher, Paul B.;Sarkar, Devanand
了解肝细胞癌（HCC）的分子发病机制将有助于开发针对这一致命疾病的有效治疗方法。我们最近发现，与正常肝脏相比，细胞转录因子Late SV 40因子（LSF）在90%以上的人HCC病例中过表达，并在肝癌发生中起着重要作用。骨桥蛋白（OPN）在转录水平上调，在介导LSF的致癌功能中起重要作用。本研究旨在通过分析LSF调控的信号通路，更好地了解LSF的功能。进行磷酸化受体酪氨酸激酶（RTK）阵列以鉴定哪些受体酪氨酸激酶被LSF激活。使用组织芯片进行免疫组织化学分析以建立HCC患者中LSF、OPN和磷酸化-c-Met水平之间的相关性。进行免疫共沉淀分析以检查OPN诱导的CD 44和c-Met相互作用。在体外和体内使用裸鼠异种移植模型进行了使用化学品和siRNA的抑制研究，以确定c-Met活化在介导LSF功能中的重要性。由LSF诱导的分泌型OPN通过OPN与其细胞表面受体CD 44之间的潜在相互作用激活c-Met。HCC患者LSF、OPN和活化c-Met水平之间存在显著相关性。在裸鼠异种移植研究中，c-Met的化学或遗传抑制导致LSF介导的肿瘤发生和转移的显著消除。目前的研究结果阐明了一种新的途径c-Met激活在肝癌的发生和支持的理由，使用c-Met抑制剂作为潜在的肝癌治疗。
Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) would facilitate development of targeted and effective therapies for this fatal disease. We recently demonstrated that the cellular transcription factor Late SV40 Factor (LSF) is overexpressed in more than 90% of human HCC cases, compared to normal liver, and plays a seminal role in hepatocarcinogenesis. LSF transcriptionally upregulates osteopontin (OPN) that plays a significant role in mediating the oncogenic function of LSF. The present study aims at a better understanding of LSF function by analyzing the signaling pathway modulated by LSF. Phospho-receptor tyrosine kinase (RTK) array was performed to identify which receptor tyrosine kinases are activated by LSF. Immunohistochemical analysis using tissue microarray was performed to establish correlation among LSF, OPN and phospho-c-Met levels in HCC patients. Co-immunoprecipitation analysis was performed to check OPN-induced CD44 and c-Met interaction. Inhibition studies using chemicals and siRNAs were performed in vitro and in vivo using nude mice xenograft models to establish the importance of c-Met activation in mediating LSF function. Secreted OPN, induced by LSF, activates c-Met via a potential interaction between OPN and its cell surface receptor CD44. A significant correlation was observed among LSF, OPN and activated c-Met levels in HCC patients. Chemical or genetic inhibition of c-Met resulted in profound abrogation of LSF-mediated tumorigenesis and metastasis in nude mice xenograft studies. The present findings elucidate a novel pathway of c-Met activation during hepatocarcinogenesis and support the rationale of using c-Met inhibitors as potential HCC therapeutics.
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影响因子：
64.8
作者：
Boccaccio, C;Sabatino, G;Comoglio, PM
通讯作者：
Comoglio, PM
通过细胞附着激活 Met 受体可诱导并维持转基因小鼠的肝细胞癌。
影响因子：
7.8
作者：
Wang, R;Ferrell, DL;Faouzi, S;Maher, JJ;Bishop, JM
通讯作者：
Bishop, JM
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
3.3
作者：
Orian-Rousseau, Veronique;Morrison, Helen;Ponta, Helmut
通讯作者：
Ponta, Helmut
影响因子：
10.5
作者：
Orian-Rousseau, V;Chen, LF;Ponta, H
通讯作者：
Ponta, H