Hippo cooperates with p53 to maintain foregut homeostasis and suppress the malignant transformation of foregut basal progenitor cells

• 成果类型: Article
• 署名作者: Jiang, Yu; Huang, Haidi; Liu, Jiangying; Luo, Dan; Mu, Rongzi; Yuan, Jianghong; Lin, Jihong; Chen, Qiyue; Tao, Wufan; Yang, Ling; Zhang, Man; Zhang, Pingping; Fang, Fengqin; Xu, Jianming; Gong, Qingqiu; Xie, Zhiping; Zhang, Yongchun
• 署名单位: Shanghai Jiao Tong University; Shanghai Jiao Tong University; Fujian Medical University; Fujian Medical University; Fujian Medical University; Fudan University; Fudan University; Inner Mongolia Medical University; Inner Mongolia Medical University; Guangzhou Medical University; Shanghai Jiao Tong University; Baylor College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10946
• DOI: 10.1073/pnas.2320559121
• 发表日期: 2024-03-01
• 关键词: stem-cells; tissue homeostasis; esophageal; carcinoma; PATHWAY; sox2; cancer; mst1; inactivation; activation

摘要

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2- deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes- associated protein (Yap)- dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen- induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.