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

Moravcikova, Erika; Krepela, Evzen; Donnenberg, Vera S; Donnenberg, Albert D; Benkova, Kamila; Rabachini de Almeida, Tatiana; Fernández Marrero, Yuniel; Bachmann, Daniel; Kaufmann, Thomas (2017). BOK displays cell death-independent tumor suppressor activity in non-small cell lung carcinoma. International journal of cancer, 141(10), pp. 2050-2061. Wiley-Blackwell 10.1002/ijc.30906

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Since 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. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Rabachini de Almeida, Tatiana; Fernández Marrero, Yuniel; Bachmann, Daniel and Kaufmann, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Jana Berger

Date Deposited:

19 Oct 2017 15:27

Last Modified:

16 Nov 2018 02:30

Publisher DOI:

10.1002/ijc.30906

PubMed ID:

28744854

Uncontrolled Keywords:

BOK Bcl-2 family Non-small cell lung carcinoma apoptosis epithelial-to-mesenchymal transition

BORIS DOI:

10.7892/boris.102410

URI:

https://boris.unibe.ch/id/eprint/102410

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