Department of Hernia and Abdominal Wall Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China.
Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1055-1062. doi: 10.26355/eurrev_201902_16993.
Hypoxia-inducible factor 1α (HIF-1α) functions importantly in the development of colorectal cancer. HIF-1α is induced by some cytokines and growth factors and is also regulated by another kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. Meanwhile, inhibiting HIF-1α expression can inhibit the development of colorectal cancer. The aim of this study was to explore the effect of epidermal growth factor (EGF) on the activation of signal transducer and activator of transcription 3 (STAT3) in human colorectal cancer cells SW480. In addition, the underlying mechanism of the STAT3 signaling pathway in regulating HIF-1α and further affecting tumorigenesis and metastasis was investigated.
Immunofluorescence and Western blotting were used to detect the activation of STAT3 by EGF in human colorectal cancer cells SW480. SW480 cells were transfected with STAT3 siRNA or treated with STAT3 inhibitor Niclosamide, and then stimulated with EGF to change the expressions of STAT3 and p-STAT3. The expression level of HIF-1α mRNA in SW480 cells was detected by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). In addition, transwell assay and tumor formation experiments were performed to validate whether STAT3 and HIF-1α affected SW480 through EGF.
STAT3 was not activated in SW480 cells in vitro. EGF induced STAT3 activation and enhanced its phosphorylation level, so that it shuttled into the nucleus. Phosphorylated activation of STAT3 was a necessary condition for EGF to induce HIF-1α up-regulation. Both HIF-1α and EGF-induced phosphorylation of STAT3 could significantly promote the proliferation and metastasis of SW480, and enhance tumorigenesis.
In SW480 cells, EGF regulated HIF-1α through the STAT3 phosphorylation pathway, eventually promoting the occurrence and metastasis of colorectal cancer.
缺氧诱导因子 1α（HIF-1α）在结直肠癌的发展中起着重要作用。HIF-1α 受一些细胞因子和生长因子诱导，也受另一种激酶/信号转导和转录激活物（JAK/STAT）信号通路的调节。同时，抑制 HIF-1α 的表达可以抑制结直肠癌的发展。本研究旨在探讨表皮生长因子（EGF）对人结直肠癌细胞 SW480 中信号转导和转录激活物 3（STAT3）激活的影响。此外，还研究了 STAT3 信号通路在调节 HIF-1α 以及进一步影响肿瘤发生和转移中的潜在机制。
采用免疫荧光和 Western blot 检测 EGF 对人结直肠癌细胞 SW480 中 STAT3 的激活作用。SW480 细胞转染 STAT3 siRNA 或用 STAT3 抑制剂 Niclosamide 处理，然后用 EGF 刺激，改变 STAT3 和 p-STAT3 的表达。采用逆转录-聚合酶链反应（RT-PCR）检测 SW480 细胞中 HIF-1α mRNA 的表达水平。此外，还进行了 Transwell 测定和肿瘤形成实验，以验证 STAT3 和 HIF-1α 是否通过 EGF 影响 SW480。
STAT3 在体外的 SW480 细胞中未被激活。EGF 诱导 STAT3 激活并增强其磷酸化水平，使其易位入核。磷酸化激活的 STAT3 是 EGF 诱导 HIF-1α 上调的必要条件。HIF-1α 和 EGF 诱导的 STAT3 磷酸化均能显著促进 SW480 的增殖和转移，并增强肿瘤发生。
在 SW480 细胞中，EGF 通过 STAT3 磷酸化途径调节 HIF-1α，最终促进结直肠癌的发生和转移。
