Cancer Res：揭示引发肝癌的新型驱动器—基因AEG-1

我们都知道，炎性往往是许多慢性疾病背后的驱动力，尤其是肝癌，其通常是由于某些因素引发的慢性炎症而引起的，这些因素包括病毒性肝炎和酒精等，而应对肝癌并没有有效的疗法；如今来自弗吉尼亚联邦大学梅西癌症中心（音译）的研究人员通过临床前试验首次揭示，阻断一种名为星形胶质细胞上调基因-1（AEG-1）的表达就可以通过调节炎性来抑制肝癌的发生和发展，该项研究刊登于国际杂志Cancer Research上，或为开发新型肝癌疗法提供新希望。
Devanand Sarkar博士表示，文章中我们开发了一种不能长效表达AEG-1基因的小鼠模型，即不能在大多数癌症中进行表达；缺失AEG-1时小鼠会对肝癌发生产生耐受，并且缺失AEG-1的效应会保护小鼠免于引发衰老相关的炎性症状及肿瘤形成。AEG-1在转录因子NF-kB的激活过程中扮演着重要角色，NF-kB是一种可以调节免疫反应，比如炎症等的蛋白质复合物。
随着研究的深入，研究者就发现AEG-1在通过 NF-kB信号通路调节炎症上扮演着重要作用，而利用特殊药物或方法阻断AEG-1或许就可以帮助开发和炎症相关的一系列疾病的新型靶向疗法；此前研究者假设，AEG-1或许是肝癌转移和发展所必须的成分，但是并不是原发性肿瘤形成的关键子，然而当前的研究指出，AEG-1可以通过与NF-kB的作用引起肝癌的发生，另外研究者还发现，NF-kB和AEG-1的相互作用不仅会在癌细胞中发生，而且在癌症周围组织的细胞中也会发生，这就表明AEG-1不仅可以调节免疫功能，而且还可以调节慢性炎性疾病的发生。
目前研究人员正在研发阻断AEG-1表达的新型药物分子，揭示AEG-1的角色或许为揭示炎性和免疫调节提供新的思路，也为开发治疗慢性炎性疾病及癌症的靶向疗法提供新的希望。（转化医学网360zhyx.com）
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Genetic deletion of AEG-1 prevents hepatocarcinogenesis
Cancer Research doi: 10.1158/0008-5472.CAN-14-1357
Chadia L Robertson1, Jyoti Srivastava1, Ayesha Siddiq2, Rachel Gredler3, Luni Emdad4, Devaraja Rajasekaran1, Maaged Akiel2, Xue-Ning Shen3, Chunqing Guo5, Shah Giashuddin6, Xiang-Yang Wang5, Shobha Ghosh7, Mark A Subler5, Jolene J Windle5, Paul B. Fisher8, and Devanand Sarkar4,*
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-kB in liver macrophages. Since AEG-1 is an essential component of NF-kB 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 B-catenin, compared to wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-kB 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-kB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-kB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.