Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma

被引:72
作者
Li, Na [1 ]
Li, Yang [1 ]
Li, Zengxun [1 ]
Huang, Chongbiao [1 ]
Yang, Yanhui [2 ,3 ]
Lang, Mingxiao [1 ]
Cao, Junli [1 ]
Jiang, Wenna [1 ]
Xu, Yu [1 ]
Dong, Jie [1 ]
Ren, He [1 ]
机构
[1] Tianjin Med Univ, Canc Inst & Hosp, Dept Pancreat Canc, Key Lab Canc Prevent & Therapy,Natl Clin Res Ctr, Tianjin 300060, Peoples R China
[2] Tianjin Med Univ, Key Lab Hormones & Dev, Minist Hlth, Tianjin Key Lab Metab Dis,Tianjin Metab Dis Hosp, Tianjin 300070, Peoples R China
[3] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin 300070, Peoples R China
基金
中国国家自然科学基金;
关键词
PDAC; monocytes/macrophages; PSCs; HIF-1; CCL2; MONOCYTE CHEMOATTRACTANT PROTEIN-1; TUMOR PROGRESSION; CANCER; EXPRESSION; GENE; THERAPY; MCP-1;
D O I
10.3390/ijms17060799
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1 alpha and HIF-1 beta, in which HIF-1 beta is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with the degree of inflammation in the tumor region, but the exact mechanism remains unclear. This study aims to identify the molecular mechanism of recruiting monocytes/macrophages by HIF-1 alpha in pancreatic ductal adenocarcinoma (PDAC) and the effects of macrophages on pancreatic stellate cells (PSCs). Immunohistochemistry (IHC) was performed for cluster of differentiation 68 (CD68), HIF-1 alpha, and chemical chemokines 2 (CCL2). Western blot, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation assay, and The Cancer Genome Atlas (TCGA) were used to verify the correlation between HIF-1 alpha and CCL2 at protein and nucleic acid levels. Monocytes/macrophages were co-cultured with PSCs to observe their interaction. Samples showed significant correlation between CD68 and HIF-1 alpha (t-test, p < 0.05). HIF-1 alpha recruited monocytes/macrophages by promoting CCL2 secretion. Moreover, macrophages could accelerate the activation of PSCs. HIF-1 alpha might promote inflammation and fibrosis of PDAC through CCL2 secretion, which may provide a novel target to treat PDAC patients.
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页数:12
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