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Int J Cancer. 2017 Nov 15;141(10):2050-2061. doi: 10.1002/ijc.30906. Epub 2017 Aug 7.

BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma.

Author information

1
Institute of Pharmacology, Faculty of Medicine, University of Bern, Bern, Switzerland.
2
Department of Cardiothoracic Surgery, School of Medicine, University of Pittsburgh, PA.
3
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
4
Department of Medicine, School of Medicine, University of Pittsburgh, PA.
5
Department of Pathology, Hospital Bulovka, Prague, Czech Republic.

Abstract

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

PMID:
28744854
PMCID:
PMC5763244
DOI:
10.1002/ijc.30906
[Indexed for MEDLINE]
Free PMC Article

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