Regulation of Pro-apoptotic and Anti-apoptotic Factors in Obesity-Related Esophageal Adenocarcinoma

Abstract Background: Obesity is a risk factor for esophageal adenocarcinoma (EAC). It is associated with increased levels of free fatty acids (FFA), leading to insulin resistance and increased expression of insulin like growth factor-1 (IGF-1) and diacylglycerol (DAG). The objective of the study is to investigate the role of apoptotic factors in control and EAC tissues in both relation to this signaling pathway in obese and non-obese patients. Methods: We included 23 obese and nonobese patients with EAC or with or without Barrett’s esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-d, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students’ t-test between two groups. Results: Our results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-d, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity. Conclusion: Patients with EAC had increased expression of cIAP2 and FLIP, and PKC-d which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma.