Journal
JOURNAL OF THORACIC ONCOLOGY
Volume 4, Issue 4, Pages 455-462Publisher
ELSEVIER SCIENCE INC
DOI: 10.1097/JTO.0b013e31819c791a
Keywords
Esophageal adenocarcinoma; INHBA; Activin; Epigenetic regulation
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Funding
- National Cancer Institute (NCI) [EDRN 051717]
- National Institute of Health through the University of Michigan's Cancer Center [5 P30 CA46592]
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Introduction: The expression, mechanisms of regulation, and functional impact of activin (INHBA) in esophageal adenocarcinoma (EAC) have not been fully defined. Methods: INHBA expression was examined in 46 esophageal samples (nine Barrett's metaplasia (BM); seven BM/low-grade dysplasia; eight low-grade dysplasia; seven high-grade dysplasia; 15 EAC) using oligonucleotide microarrays and real-time reverse transcription-polymerase chain reaction (RT-PCR) and in 90 tissue samples (79 EAC; 8 dysplastic; 3 BM) using immunohistochemistry (IHC). The proliferation of EAC cell lines FLO and OE-33 was examined after treatment with exogenous activin. The proliferation of OE-33 was also examined after treatment with the activin inhibitor follistatin and INHBA-targeting siRNA. OE-33 and FLO cells were treated with 5-aza-2'deoxycytidine (5-AZA) and trichostatin A to investigate the role of epigenetic regulation in INHBA expression. Results: Primary EACs expressed 5.7-times more INHBA mRNA than BM samples on oligonucleotide microarray. Transcript overexpression in EAC relative to BM was confirmed on real-time RT-PCR. IHC suggested higher INHBA protein expression in EAC (69.6%) than in the dysplastic (37.5%) and BM samples (33.3%). FLO and OE-33 treated with activin demonstrated increased proliferation, and OE-33 cells treated with follistatin and INHBA-targeting siRNA demonstrated reduced proliferation, relative to untreated controls. Treatment of FLO cells with trichostatin A and 5-AZA up-regulated INHBA mRNA and protein production by real time RT-PCR and IHC. Conclusions: INHBA is overexpressed in EAC relative to dysplastic and BM tissue. INHBA overexpression may promote cell proliferation and may be affected by promoter demethylation and histone acetylation in EAC cell lines.
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