Qiao Lili, Hu Yuanyuan, Xu Lei, Deng Guodong, Yu Xiaohong, Zheng Wei, Yang Yanan, Yuan Hui, Jiang Wei, Yu Xiying
Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Current address: Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.
Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Cell Mol Gastroenterol Hepatol. 2025 May 29;19(9):101549. doi: 10.1016/j.jcmgh.2025.101549.
BACKGROUND & AIMS: Tissue mechanics involved in carcinogenesis by regulating cell morphology and structure, cell-cell, and cell-extracellular matrix (ECM) interactions are not fully understood. Plectin, a cytolinker and a critical component of the cell-ECM adhesion complex hemidesmosome (HD), plays an important role in the regulation of epithelial tissue mechanics, but its functions in carcinogenesis remain elusive.
We used cellular and molecular methods and multiple systems, including a 2-dimensional (2-D) esophageal keratinocyte Ca-dependent differentiation system, a 3-dimensional (3-D) esophageal keratinocyte organoid system, and tissue samples of normal rat and human esophageal stratified squamous epithelium (SSE), N-nitroso-N-methylbenzylamine (NMBzA)-induced rat esophageal squamous cell carcinoma (ESCC), and human ESCC, to determine the role(s) of plectin in regulating SSE homeostasis and ESCC carcinogenesis.
We show that plectin is ubiquitously expressed in all proliferative and differentiative cell types in esophageal SSE. However, the localization of plectin in different cell types is controlled by plectin crosslinking to different macromolecular structures, such as HD, desmosome (DSM), and cytoskeletal filaments, and its expression is regulated by the ESCC oncogenic drivers and transcription factors, p63 and/or Notch1. Plectin functions by coupling plectin-associated HD, DSM, and cytoskeletal components together with plectin regulators p63 and Notch1, to maintain cell anchorage, proliferation/differentiation, and stratification of esophageal SSE tissue homeostasis. Perturbation of plectin expression and localization leads to the disruption of SSE homeostasis and the involvement in ESCC carcinogenesis.
Plectin is involved in maintaining SSE homeostasis, and misexpression of plectin through its genetic alterations or transcriptional dysregulations perturbs the compositions, stoichiometries, and localizations of plectin, HD, DSM, and the cytoskeleton underlying the oncogenic characteristics of plectin.
组织力学通过调节细胞形态与结构、细胞-细胞以及细胞-细胞外基质（ECM）相互作用参与致癌过程，但尚未完全明确。网蛋白是一种细胞连接蛋白，也是细胞-ECM黏附复合体半桥粒（HD）的关键组成部分，在调节上皮组织力学方面发挥重要作用，但其在致癌过程中的功能仍不明确。
我们采用细胞和分子方法以及多种系统，包括二维（2-D）食管角质形成细胞钙依赖分化系统、三维（3-D）食管角质形成细胞类器官系统，以及正常大鼠和人食管复层鳞状上皮（SSE）、N-亚硝基-N-甲基苄胺（NMBzA）诱导的大鼠食管鳞状细胞癌（ESCC）和人ESCC的组织样本，以确定网蛋白在调节SSE稳态和ESCC致癌过程中的作用。
我们发现网蛋白在食管SSE的所有增殖和分化细胞类型中普遍表达。然而，网蛋白在不同细胞类型中的定位受其与不同大分子结构（如HD、桥粒（DSM）和细胞骨架丝）交联的控制，其表达受ESCC致癌驱动因子和转录因子p63和/或Notch1调节。网蛋白通过将与网蛋白相关的HD、DSM和细胞骨架成分与网蛋白调节因子p63和Notch1耦合发挥作用，以维持食管SSE组织稳态的细胞锚定、增殖/分化和分层。网蛋白表达和定位的扰动会导致SSE稳态的破坏并参与ESCC致癌过程。
网蛋白参与维持SSE稳态，通过基因改变或转录失调导致的网蛋白错误表达会扰乱网蛋白、HD、DSM和细胞骨架的组成、化学计量和定位，这些是网蛋白致癌特性的基础。
