Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma.
Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma.
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发表时间：
2001-08
期刊：
影响因子：
11.2
通讯作者：
G. Dong;Zhong Chen;Zhi-yu Li;N. Yeh;C. Bancroft;C. Waes
中科院分区：
文献类型：
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作者：
G. Dong;Zhong Chen;Zhi-yu Li;N. Yeh;C. Bancroft;C. Waes
肝细胞生长因子(HGF)/分散因子的促血管生成活性与其刺激内皮细胞趋化、迁移、增殖和毛细血管形成的能力密切相关。然而，HGF作为旁分泌因子在调节肿瘤细胞血管生成因子表达方面的潜力并未被广泛认识。我们观察到头颈部鳞状细胞癌(HNSCC)患者血清中血管生成因子白介素8(IL-8)和血管内皮生长因子(VEGF)水平的升高与HGF的升高有关，并推测HGF可能通过激活HNSCC细胞表达的c-Met受体来调节肿瘤细胞血管生成因子的产生。为了验证这一假设，我们通过一组原代角质形成细胞和HNSCC株检测了HGF处理对IL-8和VEGF表达的影响。在所测试的8个HNSCC系中，HGF诱导IL-8和/或VEGF细胞因子的产生呈剂量依赖性增加，这在正常角质形成细胞中没有观察到。此外，HGF还上调了6株HNSCC中3株IL-8和5株HNSCC中VEGF的表达。HGF诱导这些因子的增加与HNSCC中c-Met的磷酸化增加相对应。HGF诱导的丝裂原活化蛋白/细胞外信号调节激酶(MEK)通路底物p42/p44(ERK)和磷脂酰肌醇3‘-激酶(PI3K)通路底物Akt的磷酸化为HNSCC中MEK和PI3K通路的下游激活提供了证据。MEK(U0126)和PI3K(LY294002)抑制剂分别阻断P42/P44(ERK)和Akt，并部分阻断HGF诱导的IL-8和VEGF的产生，而U0126和LY294002联合应用则完全抑制UMSCC-11A表达IL-8和VEGF。我们的结果表明，HGF可以通过MEK和PI3K依赖的途径促进肿瘤细胞中血管生成因子的表达。了解肿瘤和宿主细胞之间的HGF/Met旁分泌调节机制可能为针对血管生成的治疗提供关键信息。
The proangiogenic activity of hepatocyte growth factor (HGF)/scatter factor has been closely associated with its ability to stimulate endothelial cell chemotaxis, migration, proliferation, and capillary formation. However, the potential of HGF as a paracrine factor in regulating the expression of angiogenesis factors by tumor cells is not widely appreciated. We observed that increased HGF was correlated with higher levels of angiogenesis factors interleukin (IL)-8 and vascular endothelial growth factor (VEGF) in serum of patients with head and neck squamous cell carcinoma (HNSCC) as compared with that in normal volunteers and hypothesized that HGF may regulate angiogenesis factor production by tumor cells through the activation of its receptor c-Met, which is expressed by HNSCC cells. To test this hypothesis, we examined the effect of HGF treatment on IL-8 and VEGF expression by a panel of primary keratinocytes and HNSCC lines. HGF induced a significant dose-dependent increase in IL-8 and/or VEGF cytokine production in eight HNSCC lines tested, which is not observed in normal keratinocytes. In addition, HGF increased mRNA expression of IL-8 in 3 of 6 and VEGF in 5 of 6 HNSCC lines. The increase in induction of these factors by HGF corresponded to an increase in phosphorylation of c-Met in HNSCC. HGF-induced phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) pathway substrate p42/p44(erk) and phosphatidylinositol 3'-kinase (PI3K) pathway substrate Akt provided evidence for downstream activation of MEK and PI3K pathways in HNSCC. Inhibitors of MEK (U0126) and PI3K (LY294002) blocked p42/p44(erk) and Akt, respectively, and partially blocked HGF-induced production of IL-8 and VEGF, whereas the combination of U0126 and LY294002 completely inhibited expression of IL-8 and VEGF by UMSCC-11A. Our results demonstrate that HGF can promote expression of angiogenesis factors in tumor cells through both MEK- and PI3K-dependent pathways. Understanding HGF/Met paracrine regulatory mechanisms between tumor and host cells may provide critical information for targeting of therapies against angiogenesis.