亚硝酰胺类化合物是引起胃癌的关键膳食因素。肿瘤干细胞对肿瘤的发生、发展起决定性作用。目前从胃癌干细胞角度探讨亚硝酰胺诱发胃癌的分子机制及其干预研究未见报道。我们前期研究发现慢性甲基硝基亚硝基胍(MNNG)暴露诱导人正常胃粘膜上皮细胞恶性转化且具有胃癌干细胞样特性，此表型与下调KLF4、上调ΔNp63α及激活Notch通路有关；异硫氰酸苯乙酯(PEITC)可抑制恶转的胃癌干细胞活性。然KLF4/ΔNp63α/Notch是否真正调控慢性MNNG诱导的胃癌干细胞活性及PEITC的干预效应尚属未知。本课题采用体外细胞模型和动物模型相结合，创新性地探讨KLF4/ΔNp63α/Notch通路调控慢性MNNG暴露诱导胃癌干细胞的作用机制，并在此基础上研究PEITC的干预作用。旨在从胃癌干细胞视角探索亚硝酰胺化合物诱发胃癌的分子机制并为其靶向干预提供新的重要科学依据。

N-nitrosamides are critical dietary risk factor of gastric cancer. Cancer stem cells (CSCs) play crucial role in the formation and development of cancer. To date, the action of N-nitrosamides on the induction of gastric CSCs, the underlying mechanisms as well as phenylhexyl isothiocyanate (PEITC) intervention has not been defined yet. In our preliminary studies we found that chronic N-methyl-N’-nitro-N-nitrosoguallidine (MNNG) exposure induced malignant transformation of human normal gastric epithelial cells (GES-1), among which gastric CSCs-like properties existed, along with downregulation of KLF4, upregulation of ΔNp63α, and activation of Notch signaling pathway. We also showed that PEITC inhibited the tumorsphere-formation capacity of malignant transformated GES-1 cells cultured in serum-free-medium, reduced gastric CSCs markers’ expression, upregulated KLF4 level, suppressed ΔNp63α expression, and prevented the activation of Notch pathway. However, the role and regulation of KLF4/ΔNp63α/Notch axis in chronic MNNG-induced gastric CSCs and PEITC intervention is unknown. Using both in vitro and nude mouse models, the proposed research will for the first time investigate the role of KLF4/ΔNp63α/Notch in MNNG-induced gastric CSCs and its regulatory mechanism. Furthermore, this research will illustrate the function of KLF4/ΔNp63α/Notch in the interventional effects of PEITC on MNNG-induced gastric CSCs. Finding from this research will provide new insights into the molecular mechanisms of KLF4/ΔNp63α/Notch in regulating MNNG-induced gastric CSCs as well as its target intervention.