Long noncoding RNA glypican 3 (GPC3) antisense transcript 1 promotes hepatocellular carcinoma progression via epigenetically activating GPC3
Long noncoding RNA glypican 3 (GPC3) antisense transcript 1 promotes hepatocellular carcinoma progression via epigenetically activating GPC3
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DOI：
10.1111/febs.13839
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发表时间：
2016-10-01
期刊：
影响因子：
5.4
通讯作者：
Cheng, Xiao-yang
中科院分区：
文献类型：
--
作者：
Zhu, Xiao-ting;Yuan, Ji-hang;Cheng, Xiao-yang
长链非编码RNA（lncRNA）在多种病理生理过程中具有重要作用，并且在许多疾病，特别是癌症中经常失调。lncRNA磷脂酰肌醇蛋白聚糖3反义转录本1（GPC 3-AS 1）已被报道为肝细胞癌（HCC）筛查的潜在生物标志物。然而，GPC 3-AS 1在HCC中的确切生物学功能及其对GPC 3的作用和调控机制尚不清楚。在这项研究中，我们观察到肝癌中GPC 3-AS 1显着上调。GPC 3-AS 1表达增加与甲胎蛋白、肿瘤大小、微血管浸润、包膜、巴塞罗那临床肝癌分期和HCC患者预后不良相关。此外，我们发现GPC 3-AS 1与P300/CBP相关因子物理相关，并将其募集到GPC 3基因体区域，从而诱导常染色质组蛋白标记的增加并激活GPC 3转录。HCC组织中GPC 3-AS 1的表达与GPC 3密切相关。功能获得和功能丧失分析表明，GPC 3-AS 1过表达增强了体外HCC细胞的增殖和迁移以及体内异种移植肿瘤的生长。GPC 3-AS 1基因敲低抑制肝癌细胞增殖和迁移。此外，GPC 3-AS 1对HCC细胞增殖和迁移的影响依赖于GPC 3的上调。总的来说，我们的研究表明GPC 3-AS 1通过表观遗传学激活GPC 3显著促进HCC进展，并将GPC 3-AS 1鉴定为HCC的潜在治疗靶点。
Long noncoding RNA (lncRNA) have critical roles in various pathophysiological processes, and are frequently dysregulated in many diseases, particularly in cancer. The lncRNA glypican 3 antisense transcript 1 (GPC3-AS1) has been reported to be a potential biomarker for hepatocellular carcinoma (HCC) screening. However, the exact biological functions of GPC3-AS1 in HCC, and its roles and regulation mechanisms regarding GPC3 are still unknown. In this study, we observed a significant upregulation of GPC3-AS1 in HCC. Increased expression of GPC3-AS1 was associated with a-fetoprotein, tumor size, microvascular invasion, encapsulation, Barcelona Clinic Liver Cancer stage, and worse prognosis of HCC patients. Furthermore, we found that GPC3-AS1 physically associated with P300/CBP-associated factor and recruited it to the GPC3 gene body region, consequently inducing an increase in euchromatic histone marks and activating GPC3 transcription. GPC3-AS1 expression was strongly correlated with GPC3 in HCC tissues. Gain-of-function and loss-of-function analyses showed that GPC3-AS1 overexpression enhanced HCC cell proliferation and migration in vitro and xenograft tumor growth in vivo. GPC3-AS1 knockdown inhibited HCC cell proliferation and migration. Moreover, the effects of GPC3-AS1 on HCC cell proliferation and migration were dependent on the upregulation of GPC3. Collectively, our studies indicate that GPC3-AS1 significantly promotes HCC progression via epigenetically activating GPC3, and identifies GPC3-AS1 as a potential therapeutic target for HCC.