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Identification of Endoglin as an epigenetically regulated tumour-suppressor gene in lung cancer
K O'Leary1, A Shia1,2, F Cavicchioli1
1Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9RY, UK.
Background:
The transforming growth factor-beta (TGF- β) pathway has been implicated in proliferation, migration and invasion of various cancers. Endoglin is a TGF-β accessory receptor that modulates signalling. We identified Endoglin as an epigenetically silenced tumour-suppressor gene in lung cancer by means of a genome-wide screening approach, then sought to characterise its effect on lung cancer progression.
Methods:
Methylation microarray and RNA sequencing were carried out on lung cancer cell lines. Epigenetic silencing of Endoglin was confirmed by methylation and expression analyses. An expression vector and a 20-gene expression panel were used to evaluate Endoglin function. Pyrosequencing was carried out on two independent cohorts comprising 112 and 202 NSCLC cases, respectively, and the impact of Endoglin methylation on overall survival (OS) was evaluated.
Results:
Methylation in the promoter region resulted in silencing of Endoglin, which could be reactivated by demethylation. Increased invasion coupled with altered EMT marker expression was observed in cell lines with an epithelial-like, but not those with a mesenchymal-like, profile when Endoglin was absent. Methylation was associated with decreased OS in stage I but not in stages II-III disease.
Conclusions:
We show that Endoglin is a common target of epigenetic silencing in lung cancer. We reveal a link between Endoglin silencing and EMT progression that might be associated with decreased survival in stage I disease.
Insights
Endoglin, a tumor suppressor, is epigenetically silenced in lung cancer, impacting cell invasion and potentially decreasing survival in early-stage disease. Reactivating Endoglin may offer therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The transforming growth factor-beta (TGF-β) pathway is crucial in cancer progression.
- Endoglin acts as a TGF-β accessory receptor, modulating its signaling.
- Endoglin was identified as an epigenetically silenced tumor suppressor in lung cancer.
Purpose of the Study:
- To investigate the role of Endoglin in lung cancer progression.
- To characterize the functional impact of Endoglin epigenetic silencing.
Main Methods:
- Genome-wide screening, methylation microarray, and RNA sequencing were employed.
- Endoglin function was assessed using expression vectors and gene panels.
- Pyrosequencing analyzed Endoglin methylation in two independent non-small cell lung cancer (NSCLC) cohorts.
Main Results:
- Promoter methylation led to Endoglin silencing, reversible by demethylation.
- Loss of Endoglin increased invasion and altered epithelial-mesenchymal transition (EMT) markers in epithelial-like lung cancer cells.
- Endoglin methylation correlated with decreased overall survival (OS) in stage I NSCLC.
Conclusions:
- Endoglin is frequently epigenetically silenced in lung cancer.
- Endoglin silencing is linked to EMT progression and reduced survival in early-stage lung cancer.
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