State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
PLoS One. 2012;7(8):e43898. doi: 10.1371/journal.pone.0043898. Epub 2012 Aug 31.
Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis, but the precise mechanisms involved remain largely unknown. Here, we investigated the mechanism of action of nicotine in human nasopharyngeal carcinoma (NPC) cells. Nicotine significantly promoted cell proliferation in a dose and time-dependent manner in human NPC cells. The mechanism studies showed that the observed stimulation of proliferation was accompanied by the nicotine-mediated simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling. Treatment of NPC cells with nicotine markedly upregulated the expression of α7AChR and HIF-1α proteins. Transfection with a α7AChR or HIF-1α-specific siRNA or a α7AChR-selective inhibitor significantly attenuated the nicotine-mediated promotion of NPC cell proliferation. Nicotine also promoted the phosphorylation of ERK1/2 but not JNK and p38 proteins, thereby induced the activation of ERK/MAPK signaling pathway. Pretreatment with an ERK-selective inhibitor effectively reduced the nicotine-induced proliferation of NPC cells. Moreover, nicotine upregulated the expression of VEGF but suppressed the expression of PEDF at mRNA and protein levels, leading to a significant increase of the ratio of VEGF/PEDF in NPC cells. Pretreatment with a α7AChR or ERK-selective inhibitor or transfection with a HIF-1α-specific siRNA in NPC cells significantly inhibited the nicotine-induced HIF-1α expression and VEGF/PEDF ratio. These results therefore indicate that nicotine promotes proliferation of human NPC cells in vitro through simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling and suggest that the related molecules such as HIF-1α might be the potential therapeutic targets for tobacco-associated diseases such as nasopharyngeal carcinomas.
尼古丁是香烟烟雾中的主要成分，可促进肿瘤生长和血管生成，但其中涉及的确切机制在很大程度上仍不清楚。在这里，我们研究了尼古丁在人鼻咽癌（NPC）细胞中的作用机制。尼古丁以剂量和时间依赖的方式显著促进人 NPC 细胞的增殖。机制研究表明，观察到的增殖刺激伴随着尼古丁介导的同时调节α7AChR、HIF-1α、ERK 和 VEGF/PEDF 信号。用尼古丁处理 NPC 细胞可显著上调α7AChR 和 HIF-1α 蛋白的表达。用α7AChR 或 HIF-1α 特异性 siRNA 或α7AChR 选择性抑制剂转染可显著减弱尼古丁介导的 NPC 细胞增殖。尼古丁还促进 ERK1/2 但不 JNK 和 p38 蛋白的磷酸化，从而诱导 ERK/MAPK 信号通路的激活。用 ERK 选择性抑制剂预处理可有效减少尼古丁诱导的 NPC 细胞增殖。此外，尼古丁上调 VEGF 的表达，但抑制 PEDF 在 mRNA 和蛋白水平的表达，导致 NPC 细胞中 VEGF/PEDF 比值显著增加。在 NPC 细胞中用α7AChR 或 ERK 选择性抑制剂预处理或用 HIF-1α 特异性 siRNA 转染可显著抑制尼古丁诱导的 HIF-1α 表达和 VEGF/PEDF 比值。因此，这些结果表明，尼古丁通过同时调节α7AChR、HIF-1α、ERK 和 VEGF/PEDF 信号来促进人 NPC 细胞在体外的增殖，并表明相关分子如 HIF-1α 可能是烟草相关疾病（如鼻咽癌）的潜在治疗靶点。
