Genetic deletion of AEG-1 prevents hepatocarcinogenesis.
Genetic deletion of AEG-1 prevents hepatocarcinogenesis.
复制标题
DOI：
10.1158/0008-5472.can-14-1357
复制
发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Robertson CL;Srivastava J;Siddiq A;Gredler R;Emdad L;Rajasekaran D;Akiel M;Shen XN;Guo C;Giashuddin S;Wang XY;Ghosh S;Subler MA;Windle JJ;Fisher PB;Sarkar D
癌基因AEG-1 （MTDH， LYRIC）的激活最近被认为与肝细胞癌（HCC）的发展有关。在小鼠中，肝癌可通过暴露于致癌物DEN而引发，这已被证明依赖于肝巨噬细胞中NF-κB的激活。由于AEG-1是NF-κB活化的重要组成部分，我们研究了缺乏AEG-1基因的小鼠对den诱导的肝癌发生的易感性。aeg -1缺陷小鼠对den诱导的HCC和肺转移表现出抗性。与野生型对照动物相比，在对生长因子信号的反应或Akt、ERK和β-catenin的激活方面没有观察到差异。然而，缺乏aeg -1的肝细胞和巨噬细胞表现出NF-κB激活的相对缺陷。机制研究表明，在肿瘤微环境中，IL-6的产生和STAT-3的激活这两种HCC发展的关键介质也存在缺陷，以及其他生物学和表观遗传学发现，证实了AEG-1支持NF-κ b介导的炎症状态，从而驱动HCC的发展。总之，我们的研究结果提供了体内证据，证明AEG-1对NF-κB激活和肝癌发生至关重要，并揭示了AEG-1在塑造肝癌发展的肿瘤微环境中的新作用。
Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Since AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of Akt, ERK and β-catenin, compared to wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL-6 production and STAT-3 activation, two key mediators of HCC development, were also deficient along with other biological and epigenetics findings in the tumor microenvironment confirming that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.