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BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma
Erika Moravcikova1,2, Evzen Krepela3, Vera S Donnenberg2
1Institute of Pharmacology, Faculty of Medicine, University of Bern, Bern, Switzerland.
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.
Insights
Bcl-2-related ovarian killer (BOK) protein is downregulated in non-small-cell lung carcinoma (NSCLC), acting as a tumor suppressor by inhibiting cancer cell migration. Restoring BOK levels may improve survival in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The Bcl-2-related ovarian killer (BOK) locus is frequently deleted in human cancers, suggesting a tumor suppressor role.
- BOK's function in non-small-cell lung carcinoma (NSCLC) remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of BOK in NSCLC development and progression.
- To explore the mechanisms underlying BOK downregulation and its functional impact in NSCLC.
Main Methods:
- Analysis of BOK protein levels in 102 primary NSCLC tumors and matched lung tissues.
- Correlation of BOK expression with clinical parameters including tumor grade and lymph node metastasis.
- In vitro studies using A549 lung adenocarcinoma cells to assess BOK's effect on cell migration and epithelial-to-mesenchymal transition (EMT).
- Investigation of epigenetic mechanisms, specifically BOK promoter methylation, in regulating BOK expression.
Main Results:
- BOK protein levels were significantly downregulated in NSCLC tumors compared to normal lung tissue (p < 0.001).
- BOK downregulation correlated with higher tumor grades and lymph node metastasis (pN1, pN2).
- Higher BOK expression was associated with longer survival in lymph node-positive patients (p = 0.002).
- BOK overexpression did not induce apoptosis but inhibited TGFβ-induced migration and EMT in A549 cells.
- BOK expression is silenced in NSCLC cells via epigenetic mechanisms, particularly promoter methylation.
Conclusions:
- BOK functions as a tumor suppressor in NSCLC by inhibiting EMT and cell migration.
- Epigenetic silencing, specifically BOK promoter methylation, contributes to its downregulation in NSCLC.
- Restoring BOK levels in tumors with low expression could potentially improve patient survival.
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