FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma
FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma
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FAM134B 通过 Akt 信号传导诱导肝细胞癌的肿瘤发生和上皮间质转化
DOI：
10.1002/1878-0261.12429
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发表时间：
2019
影响因子：
6.6
通讯作者：
Chen Xiao ping
中科院分区：
文献类型：
--
作者：
Zhang Zhao qi;Chen Jin;Huang Wan qiu;Ning Deng;Liu Qiu meng;Wang Chao;Zhang Long;Ren Li;Chu Liang;Liang Hui fang;Fan Hai ning;Zhang Bi xiang;Chen Xiao ping
FAM134b(JK-1，RETREG1)基因最先被鉴定为食管鳞癌的癌基因。然而，FAM134B在肝细胞癌(HCC)发生和上皮间充质转化(EMT)中的作用尚不清楚。在本研究中，我们研究了FAM134B在肝癌中的作用及其相关的肿瘤发生机制，以及FAM134B是如何诱导EMT的。我们检测了FAM134B在正常肝细胞系、肝癌细胞系、新鲜标本和肝癌组织芯片中的表达。对122对肝细胞癌组织芯片进行回顾性研究，分析FAM134B与临床特征的相关性。通过功能获得和丧失实验、抢救实验、Akt途径激活剂/抑制物、裸鼠移植瘤模型和裸鼠肺转移模型，研究FAM134B在体内诱导肿瘤发生和体内EMT的可能机制。FAM134B在肝细胞癌中的表达水平显著高于正常肝组织和正常肝细胞。FAM134B过表达与肿瘤大小(P=0.025)、病理血管侵犯(P=0.026)、分化程度(P=0.023)、肿瘤复发(P=0.044)、门静脉癌栓(P=0.036)显著相关。FAM134B高表达患者的总生存期和无病生存期比FAM134B非高表达患者短。此外，用shRNAs敲除FAM134B抑制了细胞的生长和运动，以及裸鼠体内肿瘤的形成和转移，这些都是通过FAM134B的过表达而促进的。我们的研究表明，癌基因Fam134bis通过AKT信号通路与随后的糖原合成酶-3β磷酸化、β-连环蛋白的积聚和Snail的稳定在肝细胞癌中发挥关键作用，从而促进肝癌的发生、转移和肿瘤转移。
Fam134b(JK‐1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of FAM134B during tumorigenesis of hepatocellular carcinoma (HCC) and in epithelial‐to‐mesenchymal transition (EMT) were previously unclear. In this study, we investigated the function of FAM134B in HCC and the related tumorigenesis mechanisms, as well as how FAM134B induces EMT. We detected the expression of FAM134B in a normal hepatic cell line, HCC cell lines, fresh specimens, and a HCC tissue microarray. A retrospective study of 122 paired HCC tissue microarrays was used to analyze the correlation between FAM134B and clinical features. Gain‐ and loss‐of‐function experiments, rescue experiments, Akt pathway activator/inhibitors, nude mice xenograft models, and nude mice lung metastasis models were used to determine the underlying mechanisms of FAM134B in inducing tumorigenesis and EMTin vitroandin vivo. The expression level of FAM134B was highly elevated in HCC, as compared with that in normal liver tissues and normal hepatic cells. Overexpression of FAM134B was significantly associated with tumor size (P= 0.025), pathological vascular invasion (P= 0.026), differentiation grade (P= 0.023), cancer recurrence (P= 0.044), and portal vein tumor thrombus (P= 0.036) in HCC. Patients with high expression of FAM134B had shorter overall survival and disease‐free survival than patients with non‐high expression of FAM134B. Furthermore, knockdown of FAM134B with shRNAs inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of FAM134B. Our study demonstrated thatFam134bis an oncogene that plays a crucial role in HCC via the Akt signaling pathway with subsequent glycogen synthase kinase‐3β phosphorylation, accumulation of β‐catenin, and stabilization of Snail, which promotes tumorigenesis, EMT, and tumor metastasis in HCC.