The TGF-β-induced up-regulation of NKG2DLs requires AKT/GSK-3β-mediated stabilization of SP1

被引：14

作者：

Chen, Xiao-Hui ^{[1
]}

Lu, Lin-lin ^{[1
]}

Ke, Hong-Peng ^{[1
]}

Liu, Zong-Cai ^{[1
]}

Wang, Hai-Fang ^{[1
]}

Wei, Wei ^{[1
]}

Qi, Yi-Fei ^{[1
]}

Wang, Hong-Sheng ^{[1
]}

Cai, Shao-Hui ^{[2
]}

Du, Jun ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Dept Microbial & Biochem Pharm, Guangzhou, Guangdong, Peoples R China

[2] Jinan Univ, Sch Pharmaceut Sci, Dept Pharmacol, Guangzhou, Guangdong, Peoples R China

来源：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE | 2017年 / 21卷 / 05期

基金：

中国国家自然科学基金;

关键词：

NK cells; SP1; NK group 2 member D; transforming growth factor beta; cancer; EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; PANCREATIC-CANCER CELLS; TRANSCRIPTIONAL REGULATION; IMMUNE-RESPONSE; PROSTATE-CANCER; DOWN-REGULATION; FACTOR FAMILY; LIGANDS; EXPRESSION;

D O I：

10.1111/jcmm.13025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Natural killer (NK) cells play an important role in preventing cancer development. NK group 2 member D (NKG2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG2DL become susceptible to an immune-dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta (TGF-beta) in regulation of NKG2DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF-beta up-regulated the expression of NKG2DLs in both PC3 and HepG2 cells. The up-regulation of NKG2DLs was characterized by increasing the expression of UL16-binding proteins (ULBPs) 1 and 2. TGF-beta treatment also increased the expression of transcription factor SP1. Knockdown of SP1 significantly attenuated TGF-beta-induced up-regulation of NKG2DLs in PC3 and HepG2 cells, suggesting that SP1 plays a key role in TGF-beta-induced up-regulation of NKG2DLs. TGF-beta treatment rapidly increased SP1 protein expression while not mRNA level. It might be due to that TGF-beta can elevate SP1 stability by activating PI3K/AKT signalling pathway, subsequently inhibiting GSK-3 beta activity and decreasing the association between SP1 and GSK-3 beta. Knockdown of GSK-3 beta further verified our findings. Taken together, these results revealed that AKT/GSK-3 beta-mediated stabilization of SP1 is required for TGF-beta induced up-regulation of NKG2DLs. Our study provided valuable evidence for exploring the tumour immune modulation function of TGF-beta.

引用

页码：860 / 870

页数：11