Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18^–/– AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18^–/– mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

中文翻译：

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Claudin-18介导的YAP活性调节肺干和祖细胞稳态和肿瘤发生

Claudins是调节细胞旁通透性和细胞极性的整体紧密连接蛋白（TJ），在癌症中常常失调。然而，它们在肿瘤进展中的作用尚不清楚。在这里，我们证明敲除Cldn18（Claud18家族成员在肺泡上皮中高度表达）会导致肺肿大，实质扩张，已知的远端肺祖细胞，肺泡上皮II型（AT2）细胞的丰度和增殖增加，激活是相关蛋白（YAP），小鼠器官增大和肿瘤发生。抑制YAP会降低Cldn18 ^{– / –的}增殖和集落形成效率（CFE）AT2细胞并阻止了肺尺寸的增加，而CLDN18过表达降低了YAP核定位，细胞增殖，CFE和YAP转录活性。CLDN18和YAP相互作用和共定位在细胞间接触，而CLDN18的丢失减少了YAP与河马激酶p-LATS1 / 2的相互作用。此外，Cldn18 ^{- / -}小鼠增加了倾向发展肺腺癌（LuAd）随着年龄的增长和人类LuAd显示的依赖阶段还原CLDN18.1。这些结果确立了CLDN18作为YAP活性的调节剂，其用于限制器官大小，祖细胞增殖和肿瘤发生，并提示了一种机制，其中TJ破坏可促进祖细胞增殖以增强损伤后的修复。