BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma
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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 07, 2017
- Source ID
- 10.1002/ijc.30906
Entities
People
- Albert D Donnenberg
- Daniel Bachmann
- Erika Moravcikova
- Evzen Krepela
- Kamila Benkova
- Tatiana Rabachini
- Thomas Kaufmann
- Vera S. Donnenberg
- Yuniel Fernandez‐marrero
Organizations
- Charles University
- National Cancer Institute
- Swiss Cancer League
- Swiss National Science Foundation
- United States Department of Defense
- University of Bern
- University of Pittsburgh