PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity
PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity
复制标题
PLAGL2-EGFR-HIF-1/2α 信号环路促进 HCC 进展和厄洛替尼不敏感
DOI：
10.1002/hep.31293
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发表时间：
2021-02-06
期刊：
影响因子：
13.5
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Hu, Weiwei;Zheng, Shufang;Yang, Yong
背景和目的肝细胞癌（HCC）是全球癌症相关死亡的第三大原因，因此是一个重大的公共卫生威胁。据报道，多形性腺瘤基因样2 （PLAGL2）在肿瘤发生中起作用。然而，其在HCC中的确切功能尚不清楚。方法和结果在本研究中，我们证明了与邻近非肿瘤组织相比，PLAGL2在HCC中表达上调，并且与总生存时间相关。我们进一步表明，PLAGL2在体外和体内都能促进HCC细胞的增殖、迁移和侵袭。PLAGL2表达与表皮生长因子受体（EGFR）表达呈正相关。在机制上，本研究表明PLAGL2作为EGFR的转录调节因子，通过EGFR- akt通路促进HCC细胞增殖、迁移和侵袭。此外，缺氧可显著诱导PLAGL2高表达，其通过EGFR促进缺氧诱导因子1/2 α亚基（HIF1/2A）的表达。因此，本研究表明，PLAGL2-EGFR-HIF1/2A信号通路促进HCC进展。更重要的是，PLAGL2的表达降低了肝癌细胞对抗egfr药物厄洛替尼的反应。PLAGL2敲低增强了对厄洛替尼的应答。结论本研究揭示了PLAGL2在HCC细胞增殖、转移和厄洛替尼不敏感中的关键作用。这表明PLAGL2可能是HCC的潜在治疗靶点。
Background and Aims Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood.Approach and Results In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib.Conclusions This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.