An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK-AKT pathway
An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK-AKT pathway
复制标题
整合素 beta4-EGFR 单元通过激活 FAK-AKT 通路增强锚定独立性，从而促进肝细胞癌肺转移
DOI：
10.1016/j.canlet.2016.03.023
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发表时间：
2016-06-28
期刊：
影响因子：
9.7
通讯作者：
Zhang, Bi-xiang
中科院分区：
文献类型：
--
作者：
Leng, Chao;Zhang, Zhan-guo;Zhang, Bi-xiang
失巢凋亡是一种程序性细胞死亡，当细胞从适当的细胞外基质中分离时发生。失巢凋亡抵抗或锚定独立性是癌症远处转移所必需的。肝细胞癌（HCC）细胞对失巢凋亡产生抗性的机制尚未完全了解。整合素β 4（ITGB 4，也称为CD 104）与许多人类癌症的进展相关。在这项研究中，我们证明了ITGB 4在HCC组织和侵袭性HCC细胞系中过表达。为了探讨ITGB 4在HCC中的作用，我们使用小干扰RNA在两种HCC细胞系HCCLM 3和HLF中抑制其表达。我们发现，ITGB 4的敲低通过抑制AKT/PKB信号转导显著增强了对失巢凋亡的易感性。此外，ITGB 4以配体非依赖性方式与表皮生长因子受体（EGFR）相互作用。EGFR的失活抑制ITGB 4促进的锚定独立性和AKT途径。进一步的研究证明ITGB 4-EGFR单元触发粘着斑激酶（FAK）以激活AKT信号通路。最后，我们证明ITGB 4的过度表达与体内HCC的肿瘤生长和肺转移呈正相关。总的来说，我们首次证明ITGB 4在肝癌组织中过表达，并通过EGFR依赖性FAK-AKT激活赋予锚定独立性来促进肝癌转移。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Anoikis, a form of programmed cell death, occurs when the cells are detached from the appropriate extracellular matrix. Anoikis resistance or anchorage independence is necessary for distant metastases of cancer. The mechanisms by which hepatocellular carcinoma (HCC) cells become resistant to anoikis are not fully understood. Integrin beta4 (ITGB4, also known as CD104) is associated with progression of many human cancers. In this study, we demonstrate that ITGB4 is over-expressed in HCC tissues and aggressive HCC cell lines. To explore the role of ITGB4 in HCC, we inhibited its expression using small interfering RNA in two HCC cell lines: HCCLM3 and HLF. We show that knockdown of ITGB4 significantly enhanced susceptibility to anoikis through inhibition of AKT/PKB signaling. Moreover, ITGB4 interacts with epidermal growth factor receptor (EGFR) in a ligand independent manner. Inactivation of EGFR inhibits the anchorage independence and AKT pathway promoted by ITGB4. Further investigation proved that the ITGB4-EGFR unit triggers the focal adhesion kinase (FAK) to activate the AKT signaling pathway. Finally, we demonstrate that over-expression of ITGB4 is positively associated with tumor growth and lung metastases of HCC in vivo. Collectively, we demonstrate for the first time that ITGB4 is overexpressed in HCC tissues and promotes metastases of HCC by conferring anchorage independence through EGFR-dependent FAK-AKT activation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.