Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6-mediated cellular behavior of human hepatocellular carcinoma.-猫眼课题宝

DOI：

10.1093/carcin/bgw004

发表时间：

2016-03

期刊：

Carcinogenesis

影响因子：

4.7

通讯作者：

中科院分区：

医学2区

文献类型：

--

作者：

Jingyu Xu;Bei Ji;Guorong Wen;Yuan Yang;Hai Jin;Xuemei Liu;R. Xie;Wenfeng Song;P. Song;Hui Dong;B. Tuo

白细胞介素6（IL6）是一种关键细胞因子，参与炎症相关肝细胞癌（HCC）的发生与发展。然而，IL6对肝癌作用的机制在很大程度上仍不明确。质子和钙离子（Ca²⁺）是两种细胞内信使离子，被认为在肿瘤发生和肿瘤进展中发挥核心作用。在本研究中，我们发现，氯化铵（NH₄Cl）酸化后，IL6刺激可显著提高人肝癌细胞Huh7和HepG2的细胞内pH恢复速率，且氯化铵酸化可诱导肝癌细胞内钙离子短暂升高。抑制钠氢交换体1（NHE1）、钠钙交换体1（NCX1）和钙调蛋白（CaM），可抑制IL6刺激诱导的细胞内pH恢复速率的增加以及氯化铵酸化诱导的细胞内钙离子升高。IL6刺激还诱导了NHE1、NCX1和CaM蛋白之间的结构相互作用。原发性人肝癌组织中NHE1、NCX1和CaM的蛋白表达水平显著高于正常肝组织。IL6上调了Huh7和HepG2细胞中NHE1、NCX1和CaM的表达。NHE1、NCX1和CaM介导了IL6对Huh7和HepG2细胞增殖、迁移和侵袭以及对裸鼠体内肝癌生长的促进作用。总之，IL6激活NHE1的功能活性，并诱导NHE1、NCX1和CaM之间的功能和结构相互作用。NHE1、NCX1和CaM之间的相互作用介导了IL6对人肝癌的影响。

Interleukin 6 (IL6) is a key cytokine involved in the development and progression of inflammation-associated hepatocellular carcinoma (HCC). However, the mechanisms of IL6 action on HCC remain largely unknown. Proton and Ca(2+) are two intracellular messenger ions, which are believed to play a central role in tumorigenesis and tumor progression. In this study, we found that IL6 stimulation markedly increased intracellualr pH recovery rates of human HCC cells, Huh7 and HepG2, after NH4Cl acidification, and the NH4Cl acidification induced transient intracellular Ca(2+) increases in the HCC cells. The inhibition of Na(+)/H(+) exchanger 1 (NHE1), Na(+)/Ca(2+) exchanger 1 (NCX1) and calmodulin (CaM) inhibited the IL6 stimulation-induced intracellular pH recovery increases and NH4Cl acidification-induced intracellular Ca(2+) increases. IL6 stimulation also induced the structural interaction of NHE1, NCX1 and CaM proteins. The protein expression levels of NHE1, NCX1 and CaM in native human HCC tissues were markedly higher than those in normal liver tissues. IL6 upregulated the expressions of NHE1, NCX1 and CaM in Huh7 and HepG2 cells. NHE1, NCX1 and CaM mediated the promotion of IL6 on the proliferation, migration and invasion of Huh7 and HepG2 cells and the growth of HCC in nude mice. In conclusion, IL6 activates the functional activity of NHE1 and induces the functional and structural interaction of NHE1, NCX1 and CaM. The interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human HCC.