ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α
ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α
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DOI：
10.3892/or.2016.5293
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发表时间：
2017-02-01
期刊：
影响因子：
4.2
通讯作者：
Yoon, Seung Kew
中科院分区：
文献类型：
--
作者：
Lee, Joon Ho;Hur, Wonhee;Yoon, Seung Kew
肝细胞癌（HCC）是第五大常见实体癌，也是癌症相关死亡的第三大常见原因。HCC的发展是一个多步骤的过程，与促进HCC侵袭和迁移并促进转移的遗传畸变相关。越来越多的证据表明肿瘤干细胞（cancer stem cells，CSCs）参与肿瘤的发生、侵袭和转移。尽管由HCC细胞的该亚群代表的癌细胞的比例极小，但CSC在癌症转移和不良预后中发挥关键作用。ELK 3（Net/SAP-2/Erp）是一种由Ras/细胞外信号调节激酶（ERK）信号通路激活的转录因子。它在各种生理过程中发挥着重要作用，包括细胞迁移、侵袭、伤口愈合、血管生成和肿瘤发生。在本研究中，我们研究了ELK 3在CD 133（+）/CD 44（+）肝癌干细胞（LCSCs）中癌细胞侵袭和转移中的作用。我们从Huh 7 HCC细胞中分离表达CD 133和CD 44的LCSC，并使用侵袭和迁移测定来评估其转移潜力。我们发现CD 133（+）/CD 44（+）细胞比非CD 133（+）/CD 44（+）细胞具有更高的转移潜能。我们还证实了ELK 3在CD 133（+）/CD 44（+）细胞中的表达上调，并且这种畸变增强了细胞的迁移和侵袭。此外，我们确定了ELK 3促进癌细胞迁移和侵袭的分子机制。我们发现ELK 3在CD 133 +/CD 44 + LCSC中表达的沉默通过调节热休克诱导因子-1 α（HIF-1 α）的表达来减弱其转移潜能。总的来说，本研究的结果表明，ELK 3过表达通过调节HIF-1 α表达促进了CD 133（+）/CD 44（+）细胞的转移，ELK 3表达的沉默减弱了CD 133（+）/CD 44（+）LCSC的转移潜力。总之，ELK 3表达的调节可能代表了一种新的治疗策略，用于预防HCC转移和侵袭。
Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133(+)/CD44(+) liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133(+)/CD44(+) cells had increased metastatic potential compared with non-CD133(+)/CD44(+) cells. We also demonstrated that ELK3 expression was upregulated in CD133(+)/CD44(+) cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133+/CD44+ LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1 alpha (HIF-1 alpha). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133(+)/CD44(+) cells by regulating HIF-1 alpha expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133(+)/CD44(+) LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion.