Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma.
Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma.
复制标题
缺氧诱导因子 1 (HIF-1) 招募巨噬细胞激活胰腺导管腺癌中的胰腺星状细胞
DOI：
10.3390/ijms17060799
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发表时间：
2016-06-03
影响因子：
5.6
通讯作者：
Ren H
中科院分区：
文献类型：
--
作者：
Li N;Li Y;Li Z;Huang C;Yang Y;Lang M;Cao J;Jiang W;Xu Y;Dong J;Ren H
缺氧诱导因子1（HIF-1）是由HIF-1α和HIF-1β两个亚基组成的转录因子，其中HIF-1β为组成型表达。 HIF-1 上调多种缺氧反应蛋白，包括血管生成因子、糖酵解酶和细胞存活蛋白。 HIF-1也与肿瘤区域的炎症程度相关，但具体机制仍不清楚。本研究旨在明确胰腺导管腺癌（PDAC）中 HIF-1α 募集单核细胞/巨噬细胞的分子机制以及巨噬细胞对胰腺星状细胞（PSC）的影响。对分化簇 68 (CD68)、HIF-1α 和化学趋化因子 2 (CCL2) 进行免疫组织化学 (IHC)。使用蛋白质印迹、实时定量逆转录聚合酶链反应（qRT-PCR）、染色质免疫沉淀测定和癌症基因组图谱（TCGA）来验证HIF-1α和CCL2在蛋白质和核酸水平上的相关性。将单核细胞/巨噬细胞与 PSC 共培养以观察它们的相互作用。样本显示 CD68 和 HIF-1α 之间存在显着相关性（t 检验，p < 0.05）。 HIF-1α 通过促进 CCL2 分泌来招募单核细胞/巨噬细胞。此外，巨噬细胞可以加速 PSC 的激活。 HIF-1α可能通过CCL2分泌促进PDAC炎症和纤维化，这可能为治疗PDAC患者提供新的靶点。
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.