As the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small-cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (p < 0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (p = 0.004, n = 35) and three (p = 0.031, n = 39) as well as in tumors with metastases to hilar (pN1) (p = 0.047, n = 31) and mediastinal/subcarinal lymph nodes (pN2) (p = 0.021, n = 18) as opposed to grade one tumors (p = 0.688, n = 7) and tumors without lymph node metastases (p = 0.112, n = 51). Importantly, in lymph node-positive patients, BOK expression greater than the median value was associated with longer survival (p = 0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients.

• Keywords
• BOK, Bcl-2 family, apoptosis, epithelial-to-mesenchymal transition, non-small-cell lung carcinoma,
• MeSH
• Adenocarcinoma genetics   metabolism   secondary   MeSH
• Apoptosis * MeSH
• Epithelial-Mesenchymal Transition MeSH
• Humans MeSH
• Lymphatic Metastasis MeSH
• Survival Rate MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Tumor Cells, Cultured MeSH
• Lung Neoplasms genetics   metabolism   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung genetics   metabolism   secondary   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins c-bcl-2 genetics   metabolism   MeSH
• Carcinoma, Squamous Cell genetics   metabolism   secondary   MeSH
• Neoplasm Staging MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• BOK protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Proto-Oncogene Proteins c-bcl-2 MeSH