失巢
蛋白激酶B
癌症研究
焦点粘着
生物
表皮生长因子受体
信号转导
基因敲除
转移
细胞生物学
癌症
细胞培养
遗传学
作者
Chao Leng,Zhanguo Zhang,Weixun Chen,Hongping Luo,Jia Song,Dong Wang,Xuan-ru Zhu,Xiaoping Chen,Huifang Liang,Bixiang Zhang
出处
期刊:Cancer Letters
[Elsevier]
日期:2016-06-01
卷期号:376 (1): 188-196
被引量:70
标识
DOI:10.1016/j.canlet.2016.03.023
摘要
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.
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