A Novel lncRNA IHS Promotes Tumor Proliferation and Metastasis in HCC by Regulating the ERK- and AKT/GSK-3β-Signaling Pathways
A Novel lncRNA IHS Promotes Tumor Proliferation and Metastasis in HCC by Regulating the ERK- and AKT/GSK-3β-Signaling Pathways
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新型 lncRNA IHS 通过调节 ERK 和 AKT/GSK-3 β 信号通路促进 HCC 肿瘤增殖和转移
DOI：
10.1016/j.omtn.2019.04.021
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发表时间：
2019-06-07
影响因子：
8.8
通讯作者：
Xiao, Zhiyu
中科院分区：
文献类型：
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作者：
Chen, Zheng;Yu, Wei;Xiao, Zhiyu
长链非编码RNA（longnoncodingRNA，lncRNA）参与多种生物学过程，如肿瘤增殖和转移。近年来有报道称，B型肝炎病毒X蛋白（HBx）与SMYD 3在促进肝细胞癌（HCC）增殖和转移中有密切关系。然而，HBx-SMYD 3的确切致癌机制仍然未知。在本研究中，我们通过lncRNA微阵列分析，鉴定了一种新的lncRNA，它被HBx和SMYD 3共同调控，我们将其命名为lncIHS（lncRNA intersection between HBx microarray and SMYD 3 microarray）。lncIHS在肝癌组织中过表达，降低了肝癌患者的生存率。敲低lncIHS抑制HCC细胞迁移、侵袭和增殖，反之亦然。进一步的研究表明，lncIHS正调控上皮间质转化（EMT）相关标志物c-Myc和Cyclin D1的表达，以及ERK和AKT信号通路的激活。IncIHS通过ERK和AKT信号通路发挥其致癌作用。此外，从转录组测序分析和质谱分析的结果表明，lncIHS调控的ERK和AKT信号通路的上游分子的多个基因。因此，我们的研究结果表明，ERK和AKT信号通过HBx-SMYD 3下游的lncIHS调节网络，并且它们表明lncIHS可能是治疗HCC的潜在靶点。
Long noncoding RNAs (lncRNAs) are involved in a variety of biological processes such as tumor proliferation and metastasis. A close relationship between hepatitis B virus X protein (HBx) and SMYD3 in promoting the proliferation and metastasis of hepatocellular carcinoma (HCC) was recently reported. However, the exact oncogenic mechanism of HBx-SMYD3 remains unknown. In this study, by performing lncRNA microarray analysis, we identified a novel lncRNA that was regulated by both HBx and SMYD3, and we named it lncIHS (lncRNA intersection between HBx microarray and SMYD3 microarray). lncIHS was overexpressed in HCC and decreased the survival rate of HCC patients. Knockdown of lncIHS inhibited HCC cell migration, invasion, and proliferation, and vice versa. Further study showed that lncIHS positively regulated the expression of epithelial mesenchymal transition (EMT)-related markers c-Myc and Cyclin D1, as well as the activation of the ERK- and AKT-signaling pathways. lncIHS exerted its oncogenic effect through ERK and AKT signaling. Moreover, results from transcriptome-sequencing analysis and mass spectrometry showed that lncIHS regulated multiple genes that were the upstream molecules of the ERK- and AKT-signaling pathways. Therefore, our findings suggest a regulatory network of ERK and AKT signaling through lncIHS, which is downstream of HBx-SMYD3, and they indicate that lncIHS may be a potential target for treating HCC.