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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824875 | PMC |
http://dx.doi.org/10.1172/JCI90429 | DOI Listing |
Mol Med
December 2024
Department of Otorhinolaryngology/Head and Neck, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No.3 East Qingchun Road, Hangzhou, 310020, Zhejiang, China.
Background: Sleep apnea syndrome (SAS) is associated with hypertension and vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α) and the Hippo-YAP pathway are implicated in these processes, but their specific roles remain unclear. This study investigated the HIF-1α/Hippo-YAP pathway in SAS-related hypertension.
View Article and Find Full Text PDFAnal Chem
December 2024
University of Science and Technology of China, Hefei, Anhui 230026, China.
Environmental mechanical forces, such as cell membrane stress, cell extrusion, and stretch, have been proven to affect cell growth and migration. Piezo1, a mechanosensitive channel protein, responds directly to endogenous or exogenous mechanical stimuli. Here, we explored the Piezo1 distribution and microfilament morphological changes induced by mechanical forces in the tumor and normal cells.
View Article and Find Full Text PDFCancer Sci
December 2024
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.
KRAS was long deemed undruggable until the discovery of the switch-II pocket facilitated the development of specific KRAS inhibitors. Despite their introduction into clinical practice, resistance mechanisms can limit their effectiveness. Initially, tumors rely on mutant KRAS, but as they progress, they may shift to alternative pathways, resulting in intrinsic resistance.
View Article and Find Full Text PDFInt Immunopharmacol
December 2024
Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address:
Toxicology
December 2024
Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address:
Polycyclic aromatic hydrocarbons (PAHs) have been regarded as important environmental carcinogens that can cause lung cancer. However, the underlying epigenetic mechanism during PAHs-induced lung carcinogenesis has remained largely unknown. Previously, we screened some novel epigenetic regulatory genes during 3-methylcholanthrene (3-MCA)-induced lung carcinogenesis, including the potassium inwardly rectifying channel subfamily J member 15 (KCNJ15) gene.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!