The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK—an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.
LKB1与PTEN基因在胃癌发生发展中具有关键作用。LKB1作为重要的抑癌基因，其编码的丝氨酸/苏氨酸激酶可直接激活细胞代谢核心激酶AMPK。该通路通过调控E-钙黏蛋白表达，在维持上皮细胞连接稳定性中发挥重要作用。而PTEN作为人类多种癌症中高频突变的抑癌基因，是磷脂酰肌醇3-激酶（PI3K）信号通路的关键负调控因子。本研究利用H+/K+ ATP酶Cre转基因品系，实现胃壁细胞特异性Cre重组酶表达，旨在建立胃特异性LKB1与PTEN双基因功能缺失模型，从而诱导产生类人胃腺癌的胃癌发生过程。进一步研究将深入解析这些基因改变如何影响胃癌组织病理学进展、侵袭转移潜能、血管生成及肿瘤基质微环境的动态演变。实验结果表明，条件性敲除PTEN和LKB1可通过促进癌细胞增殖、血管生成和转移，为胃癌发生创造理想的肿瘤微环境。
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