Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression
Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression
复制标题
自分泌人类生长激素通过 STAT3 依赖性抑制 CLAUDIN-1 表达促进肝细胞癌细胞的侵袭性和癌症干细胞样行为
DOI：
10.3390/ijms18061274
复制
发表时间：
2017-06-01
影响因子：
5.6
通讯作者：
Lobie, Peter E.
中科院分区：
文献类型：
--
作者：
Chen, Yi-Jun;You, Ming-Liang;Lobie, Peter E.
尽管在肝细胞癌的诊断和治疗方面取得了进展，但临床结果仍然不令人满意。人生长激素(HGH)在肝细胞癌中的高表达已被报道，并与肝细胞癌患者不良的生存结局有关。在此，我们探讨了hGH在肝癌细胞系中的致癌作用机制。体外功能分析表明，hGH在这些肝癌细胞系中的强制表达促进了细胞的增殖、细胞存活、非锚定生长、细胞迁移和侵袭，正如先前报道的那样。此外，强制表达hGH可促进肝癌细胞的肿瘤干细胞样特性。强制表达hGH的肝癌细胞侵袭性和CSC样特性的增强是通过抑制紧密连接成分claudin-1的表达而实现的。一贯地，Claudin-1的表达缺失增加了肝癌细胞系的侵袭性和CSC样特性。此外，强制表达claudin-1取消了强制表达hGH的肝癌细胞株获得的侵袭性和CSC样特性。我们进一步证明，强制表达hGH通过信号转导和转录激活子3(STAT3)介导的Claudin-1转录抑制抑制了Claudin-1在肝癌细胞系中的表达。因此，我们阐明了一个新的hGH-STAT3-claudin-1轴，它与肝细胞癌的侵袭性和CSC样属性有关。抑制hGH应该被认为是阻止肝癌进展和复发的一种治疗选择。
Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism of the oncogenic effects of hGH in HCC cell lines. In vitro functional assays demonstrated that forced expression of hGH in these HCC cell lines promoted cell proliferation, cell survival, anchorage-independent growth, cell migration, and invasion, as previously reported. In addition, forced expression of hGH promoted cancer stem cell (CSC)-like properties of HCC cells. The increased invasive and CSC-like properties of HCC cells with forced expression of hGH were mediated by inhibition of the expression of the tight junction component CLAUDIN-1. Consistently, depletion of CLAUDIN-1 expression increased the invasive and CSC-like properties of HCC cell lines. Moreover, forced expression of CLAUDIN-1 abrogated the acquired invasive and CSC-like properties of HCC cell lines with forced expression of hGH. We further demonstrated that forced expression of hGH inhibited CLAUDIN-1 expression in HCC cell lines via signal transducer and activator of transcription 3 (STAT3) mediated inhibition of CLAUDIN-1 transcription. Hence, we have elucidated a novel hGH-STAT3-CLAUDIN-1 axis responsible for invasive and CSC-like properties in HCC. Inhibition of hGH should be considered as a therapeutic option to hinder progression and relapse of HCC.