HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis.
HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis.
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HBx介导的AIM2减少导致肝细胞癌转移
DOI：
10.1002/1878-0261.12090
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发表时间：
2017-09
影响因子：
6.6
通讯作者：
Yun JP
中科院分区：
文献类型：
--
作者：
Chen SL;Liu LL;Lu SX;Luo RZ;Wang CH;Wang H;Cai SH;Yang X;Xie D;Zhang CZ;Yun JP
肿瘤转移是肝细胞癌（HCC）患者高死亡率的原因。在黑色素瘤2（AIM 2）中的缺失与炎症和癌变有关，尽管其在HCC转移中的作用仍然未知。在目前的研究中，我们发现AIM 2蛋白表达在HCC细胞系和临床样本中显著降低。AIM 2的减少与较高的血清AFP水平、血管浸润、肿瘤分化差、肿瘤包膜不完整和术后生存率不利密切相关。体外研究表明，B型肝炎病毒X蛋白（HBx）在转录和翻译后水平调节AIM 2表达。HBx过表达通过增强EZH 2的稳定性，在mRNA和蛋白水平上显著阻断AIM 2的表达。此外，HBx与AIM 2相互作用，通过泛素化诱导导致AIM 2降解增加。在功能上，AIM 2的敲除增强了细胞迁移、细胞伪足的形成、伤口愈合和肿瘤转移，而AIM 2的重新引入减弱了这些功能。AIM 2的缺失诱导了上皮-间质转化（EMT）的激活。纤连蛋白1（FN 1）被发现是AIM 2的下游效应子，其表达受AIM 2的调控。FN 1的沉默显著停止了由AIM 2耗尽诱导的细胞迁移。这些数据表明，HBx诱导的AIM 2丢失与不良结局相关，并通过触发EMT过程促进HCC转移。因此，本研究的结果表明，AIM 2是B型肝炎病毒相关HCC的潜在预后生物标志物，也是肿瘤转移的可能治疗靶点。
Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis.
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TRIM11 通过 p62 依赖性选择性自噬降解 AIM2，从而抑制 AIM2 炎症小体
影响因子：
8.8
作者：
Liu, Tao;Tang, Qin;Cui, Jun
通讯作者：
Cui, Jun
影响因子：
--
作者：
Li W;Li M;Liao D;Lu X;Gu X;Zhang Q;Zhang Z;Li H
通讯作者：
Li H
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C
影响因子：
32.4
作者：
Dupaul-Chicoine, Jeremy;Arabzadeh, Azadeh;Saleh, Maya
通讯作者：
Saleh, Maya
影响因子：
7.3
作者：
Chung, Grace Tin-Yun;Lou, Wilson Pak-Kin;Lo, Kwok-Wai
通讯作者：
Lo, Kwok-Wai