Reduced Claudin-3 Expression Is Linked to Unfavorable Tumor Features and Poor Prognosis in Non-Small Cell Lung Cancer

Nina Schraps,1 Martin Reck,2 Birgit Hantzsch-Kuhn,2 Till Olchers,2 David Benjamin Ellebrecht,3 Katharina Möller,4 Christoph Fraune,4,5 Maximilian Lennartz,4 Florian Lutz,4 Martina Kluth,4 Georgia Makrypidi-Fraune,4 Ronald Simon,4 Guido Sauter,4 Stefan Steurer,4 Sönke Von Weihe3 1General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungenClinic, Grosshansdorf, Germany; 3Department of Thoracic Surgery, Airway Research Center North, German Center for Lung Research, LungenClinic, Grosshansdorf, Germany; 4Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, GermanyCorrespondence: Ronald Simon, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany, Tel +4940741057214, FAX +4940741055997, Email [email protected]: Claudin 3 (CLDN3) is a transmembrane protein which forms tight junctions (TJs) together with other claudins, occludin, and junctional adhesion molecules. Because of its membranous localization CLDN3 is a potential therapeutic target. Altered CLDN3 has been proposed as a prognostic feature in lung cancer and other tumors.Material and Methods: To better understand the prevalence of expression and its impact on the prognosis of different lung cancer subtypes, we investigated CLDN3 expression by immunohistochemistry in a set of tissue microarrays containing 858 resected lung cancers.Results: CLDN3 positivity was markedly more frequent and more intense in pulmonary adenocarcinoma (AC, 95.9% positive) than in squamous cell carcinoma (SCC, 53.3%; p< 0.0001). Among 444 ACs, CLDN3 staining was strong in 64.2%, moderate in 25.0%, weak in 6.8% and negative in 4.1%. In 214 SCCs, CLDN3 staining was strong in 6.1%, moderate in 11.7%, weak in 35.5% and negative in 46.7%. Reduced CLDN3 staining was significantly linked to advanced pT stage in both AC and SCC (p< 0.0001 each). The fraction of strongly positive cases decreased markedly from pT1 (AC: 67.6%; SCC: 11.1%) to pT4 (47.2%/1.8%). Low CLDN3 expression was also linked to nodal metastasis (p=0.0339) and R+ status (p = 0.0068) in SCCs. Absent or reduced CLDN3 staining was significantly associated with shortened overall survival in pulmonary ACs (p=0.0235) and SCCs (p=0.0330).Conclusion: It is concluded that CLDN3 expression is common in lung cancer, that its level of expression is higher in AC than in SCC, and that a reduced expression level is associated with unfavorable outcome in both SCC and AC. Once anti-CLDN3 targeted drugs should prove to be safe and efficient, NSCLC may represent a major application for such treatments.Keywords: CLDN3, NSCLC, TMA, IHC