Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 17, Issue 6, Pages -Publisher
MDPI AG
DOI: 10.3390/ijms17060799
Keywords
PDAC; monocytes/macrophages; PSCs; HIF-1; CCL2
Funding
- National Natural Science Foundation of China [81525021, 81502067, 81302082, 81272685, 31301151, 81172355, 31471340, 31470957, 81472264, 81401957]
- Key Program of Natural Science Foundation of Tianjin [11JCZDJC18400, 13YCYBYC37400]
- Major Anticancer TechnologiesR&D Program of Tianjin [12ZCDZSY16700]
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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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