Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma.
Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β 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-1α 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-1α, 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-1α 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-1α (t-test, p < 0.05). HIF-1α recruited monocytes/macrophages by promoting CCL2 secretion. Moreover, macrophages could accelerate the activation of PSCs. HIF-1α might promote inflammation and fibrosis of PDAC through CCL2 secretion, which may provide a novel target to treat PDAC patients.
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. linazys@163.com.
Na
N
Li
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. 13516239159@163.com.
Yang
Y
Li
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. 13516198199@163.com.
Zengxun
Z
Li
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. chhuang@tmu.edu.cn.
Chongbiao
C
Huang
Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital &amp; Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China. yanhuiyangyyh@gmail.com.
Yanhui
Y
Yang
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. ninoharuka@126.com.
Mingxiao
M
Lang
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. daocaorenwx@163.com.
Junli
J
Cao
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. 18234140549@163.com.
Wenna
W
Jiang
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. happyxuyu@163.com.
Yu
Y
Xu
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. dong437241269@163.com.
Jie
J
Dong
Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. renhe@tjmuch.com.
He
H
Ren
D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015415:Biomarkers; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2; D002634:Chemotaxis, Leukocyte; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000276:immunology / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D018932:Chemokine CCL2; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C067980:CD68 antigen, human; D000097382:CD68 Molecule
CCL2; HIF-1; PDAC; PSCs; monocytes/macrophages