INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France; University of Costa Rica, San José, Costa Rica.
INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France.
Cell Mol Gastroenterol Hepatol. 2020;9(2):257-276. doi: 10.1016/j.jcmgh.2019.10.007. Epub 2019 Oct 24.
BACKGROUND & AIMS: Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context.
Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated.
LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes.
H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.
胃癌主要与 CagA+幽门螺杆菌感染有关，该感染破坏胃黏膜的更新，并引发上皮-间充质转化（EMT）和肿瘤前的去分化。Hippo 通路是一种肿瘤抑制通路，其核心由大肿瘤抑制因子 2（LATS2）激酶及其底物 Yes 相关蛋白 1（YAP1）组成，在这种情况下对其进行了研究。
通过转录组学和免疫染色分析，研究了 Hippo、EMT 和肠化生标志物在人胃 AGS 和 MKN74 细胞系以及非胃源永生化 RPE1 和 HMLE 上皮细胞系受到幽门螺杆菌感染后的表达情况，并研究了感染患者和小鼠的胃组织。使用小干扰 RNA 沉默 LATS2 和 YAP1。使用转录增强相关结构域（TEAD）报告基因检测分析。评估细胞增殖和侵袭。
LATS2 和 YAP1 在感染的黏膜中共同过表达，尤其是在胃炎和肠化生中。CagA 通过幽门螺杆菌以协调的双相模式刺激 LATS2 和 YAP1，其特征是早期短暂的 YAP1 核积累和刺激 YAP1/TEAD 转录，随后核 LATS2 上调导致 YAP1 磷酸化并靶向降解。LATS2 和 YAP1 相互正向调节对方的表达。功能丧失实验表明，LATS2 限制了幽门螺杆菌诱导的 EMT 标志物表达、侵袭和肠化生，支持 LATS2 在维持胃细胞上皮表型和限制幽门螺杆菌诱导的肿瘤前变化中的作用。
幽门螺杆菌感染涉及多种信号级联反应，使黏膜稳态发生偏离，包括 Hippo LATS2/YAP1/TEAD 通路。在宿主-病原体的冲突中，会产生炎症环境以及上皮更新和分化的改变，Hippo 信号似乎是一种保护途径，限制了胃癌发展之前胃上皮细胞特性的丧失。
