SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression.
SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression.
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DOI：
10.1371/journal.pone.0121338
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hao J
中科院分区：
文献类型：
--
作者：
Gao C;Li S;Zhao T;Chen J;Ren H;Zhang H;Wang X;Lang M;Liu J;Gao S;Zhao X;Sheng J;Yuan Z;Hao J
干细胞因子（SCF）和缺氧诱导因子-1α（HIF-1α）在胰腺导管腺癌（PDAC）中均具有重要作用。本研究旨在分析PDAC标本中SCF和HIF-1α的表达及其临床病理意义，并探讨PDAC细胞体内外的分子机制。我们通过蛋白质印迹、PCR、染色质免疫沉淀（ChIP）测定和荧光素酶测定分析表明，SCF 的表达与 HIF-1α 表达显着相关。 SCF 水平还与 PDAC 样本中的淋巴结转移和病理肿瘤淋巴结转移 (pTNM) 分期相关。 SCF高表达组的存活率显着低于SCF低表达组（p<0.05）。缺氧通过缺氧诱导因子（HIF）-1α在蛋白质和RNA水平上调PDAC细胞中SCF的表达。当 HIF-1α 通过 RNA 干扰被敲除时，SCF 水平显着下降。此外，ChIP和荧光素酶结果表明HIF-1α可以直接结合SCF启动子的缺氧反应元件（HRE）区域并在缺氧下激活SCF转录。集落形成、细胞划痕和Transwell迁移实验结果表明，SCF促进缺氧条件下PANC-1细胞的增殖和侵袭。此外，在体外缺氧条件下添加外源性SCF可以挽救HIF-1α敲低后细胞增殖和侵袭能力的下调。最后，当地高辛抑制HIF-1α表达时，肿瘤体积和SCF水平下降，从而证明了体内HIF-1α与SCF之间的关系。总之，SCF是PDAC生长的重要因素。在我们的实验中，我们证明了HIF-1α的下游基因SCF可以在缺氧条件下促进PDAC的发育。因此，SCF可能是PDAC的潜在治疗靶点。
Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.
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影响因子：
8.8
作者：
Seenath, M. M.;Roberts, D.;Cawthorne, C.;Saunders, M. P.;Armstrong, G. R.;O'Dwyer, S. T.;Stratford, I. J.;Dive, C.;Renehan, A. G.
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