BACKGROUND:CCN family, comprising six members (Cyr61, CTGF, Nov, WISP-1, WISP-2, WISP-3), is involved in the stimulation of cell proliferation, migration, adhesion, angiogenesis, and tumorigenesis. Several studies have shown that expression of Cyr61, CTGF, and WISP-1 affects the tumorigenic potential of lung cancer cells in vitro. However, the correlation of expression of CCN family proteins and clinical features of lung cancer remains unknown. METHODOLOGY AND PRINCIPAL FINDINGS:In the present work, we quantified the mRNA levels of Cyr61, CTGF, and WISP-1 in samples from 60 primary lung cancers and their matched normal lung tissues by quantitative real-time PCR assay. Downregulation of the Cyr61 and CTGF genes and upregulation of the WISP-1 gene were found in primary lung cancers compared to the paired normal lung tissues. Immunohistochemistry analysis also disclosed a similar expression pattern of Cyr61, CTGF, and WISP-1 protein in paired lung cancer tissues. Statistical analysis revealed significant associations between expression of either Cyr61 or CTGF with tumor stage, tumor histology, metastasis, smoking, and family history at diagnosis. A significant correlation also existed between WISP-1 expression with tumor histology, and patient age. Moreover, expression levels of Cyr61 and CTGF correlated with survival of the lung-cancer patients. CONCLUSIONS:Our results suggest that Cyr61, CTGF, and WISP-1 might be implicated in the development and progression of primary lung cancers, and their levels might serve as valuable prognostic markers, as well as potential targets for therapeutic intervention.