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In the present study, we analyzed primary non\u2010small\u2010cell 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 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (<jats:italic>p<\/jats:italic>\u2009=\u20090.004, <jats:italic>n<\/jats:italic>\u2009=\u200935) and three (<jats:italic>p<\/jats:italic>\u2009=\u20090.031, <jats:italic>n<\/jats:italic>\u2009=\u200939) as well as in tumors with metastases to hilar (pN1) (<jats:italic>p<\/jats:italic>\u2009=\u20090.047, <jats:italic>n<\/jats:italic>\u2009=\u200931) and mediastinal\/subcarinal lymph nodes (pN2) (<jats:italic>p<\/jats:italic>\u2009=\u20090.021, <jats:italic>n<\/jats:italic>\u2009=\u200918) as opposed to grade one tumors (<jats:italic>p<\/jats:italic>\u2009=\u20090.688, <jats:italic>n<\/jats:italic>\u2009=\u20097) and tumors without lymph node metastases (<jats:italic>p<\/jats:italic>\u2009=\u20090.112, <jats:italic>n<\/jats:italic>\u2009=\u200951). Importantly, in lymph node\u2010positive patients, BOK expression greater than the median value was associated with longer survival (<jats:italic>p<\/jats:italic>\u2009=\u20090.002, Mantel test). Using <jats:italic>in vitro<\/jats:italic> approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGF\u03b2\u2010induced migration and epithelial\u2010to\u2010mesenchymal transition (EMT) in lung adenocarcinoma\u2010derived A549 cells. We have identified epigenetic mechanisms, in particular <jats:italic>BOK<\/jats:italic> 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\u2010BOK\u2010expressing tumors might favor the overall survival of NSCLC patients.<\/jats:p>","DOI":"10.1002\/ijc.30906","type":"journal-article","created":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T08:10:43Z","timestamp":1501056643000},"page":"2050-2061","source":"Crossref","is-referenced-by-count":28,"title":["BOK displays cell death\u2010independent tumor suppressor activity in non\u2010small\u2010cell lung carcinoma"],"prefix":"10.1002","volume":"141","author":[{"given":"Erika","family":"Moravcikova","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, Faculty of Medicine, University of Bern Bern Switzerland"},{"name":"Department of Cardiothoracic Surgery School of Medicine, University of Pittsburgh  PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evzen","family":"Krepela","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Experimental Oncology, First Faculty 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