STAT1 activation-induced apoptosis of esophageal squamous cell carcinoma cells in vivo
STAT1 activation-induced apoptosis of esophageal squamous cell carcinoma cells in vivo
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DOI：
10.1245/s10434-006-9274-7
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发表时间：
2007-04-01
影响因子：
3.7
通讯作者：
Sakai, Yoshiharu
中科院分区：
文献类型：
--
作者：
Kaganoi, Junichi;Watanabe, Go;Sakai, Yoshiharu
背景：诱导细胞凋亡可能是传统疗法难以治愈的癌症，如食道癌的一种很有前途的治疗方法。在本研究中，我们检测了表皮生长因子诱导的生长抑制是否是由于STAT1激活导致的食管鳞状细胞癌(SCC)细胞的凋亡，并评价了干扰素-γ能否在体内诱导癌细胞的凋亡。用包括流式细胞术在内的几种实验技术评估细胞凋亡。以白藜芦醇为标记物，用Western印迹法检测细胞分化程度。在体内，将癌细胞注射到雄性BALB/cnu/nu小鼠体内。两周后，小鼠开始接受每周四次的尾静脉注射干扰素-伽马或生理盐水。采用酶联免疫吸附试验检测肿瘤组织中干扰素-γ的浓度。结果：表皮生长因子通过STAT1激活途径引起细胞凋亡，抑制食管鳞癌细胞的生长。干扰素-γ可诱导癌细胞凋亡，但也可促进原代培养的正常食道上皮细胞分化(而不是凋亡)。结论：干扰素-γ可作为细胞因子治疗肿瘤的候选药物之一。干扰素诱导的STAT1激活可能参与了食管鳞癌细胞的凋亡和正常鳞状细胞的终末分化。对STAT1信号通路的进一步研究可能为新的食管鳞癌靶向治疗策略提供基础。
Background: The induction of apoptosis might be a promising treatment for cancers refractory to conventional therapies, such as esophageal cancer. In this study, we examined whether epidermal growth factor-induced growth inhibition results from apoptosis of esophageal squamous cell carcinoma (SCC) cells as a result of STAT1 activation and evaluated whether interferon gamma (IFN-gamma) can induce apoptosis of cancer cells in vivo.Methods: To assess the function of STAT1, we established stable transfectants expressing dominant-negative STAT1. Apoptosis was assessed by several experimental techniques, including flow cytometry. Differentiation was evaluated by Western blot test with involucrin used as a marker. In vivo, cancer cells were injected into male BALB/c nu/nu mice. Two weeks later, the mice started to receive injections of IFN-gamma or saline into a tail vein four times per week. Concentrations of IFN-gamma in the tumors were analyzed by enzyme-linked immunosorbent assay. Apoptosis was evaluated by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining.Results: Epidermal growth factor inhibited the growth of esophageal SCC cells by causing apoptosis through several pathways involving STAT1 activation. IFN-gamma induced the apoptosis of cancer cells, but it also promoted the differentiation (not apoptosis) of primary cultured cells derived from normal esophageal epithelium. IFN-gamma also inhibited the growth of xenograft tumors of esophageal SCC cells in vivo.Conclusions: Our results suggest that IFN-gamma is one candidate for cytokine-based therapy of cancer. IFN-gamma-induced STAT1 activation might be involved in the apoptosis of esophageal SCC cells and in the terminal differentiation of normal squamous cells. Further studies of STAT1 signaling pathways may provide the basis for new targeted therapeutic strategies for esophageal SCC.