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

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.

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.

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).

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.