Methylation of BNIP3 in pancreatic cancer inhibits the induction of mitochondrial-mediated tumor cell apoptosis
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Ye Li1,2,*, Xu Zhang3,4,*, Jian Yang1,*, Yi Zhang1, Dongming Zhu1,2, Lifeng Zhang1, Yanbo Zhu5, Dechun Li1,2 and Jian Zhou1,2
1Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
2Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
3Department of General Surgery, Suzhou Science & Technology Town Hospital, Suzhou 215006, China
4Department of General Surgery, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215006, China
5Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
*These authors have contributed equally to this work
Jian Zhou, email: [email protected]
Keywords: BNIP3, HIF-1α, apoptosis, methylation, pancreatic cancer
Received: April 19, 2017 Accepted: May 31, 2017 Published: June 28, 2017
Bcl-2 interacting protein 3 (BNIP3) is involved in various cellular processes and is considered a key regulator of hypoxia-induced apoptosis. In the present study, the expression of BNIP3 in pancreatic cancer tissues, the correlation with clinicopathological characteristics and prognosis and the regulation of this protein in pancreatic cancer cell lines with regard to the induction of apoptosis were investigated. BNIP3 expression was significantly lower in pancreatic cancer tissues compared with normal epithelia and was associated with tumor size, clinical stage, and lymph node metastasis. The expression of BNIP3 correlated positively to the proapoptotic protein Bax and negatively to the antiapoptotic protein Bcl-2, whereas the induction of apoptosis by BNIP3 was independent of caspase 3 and 9 activation. The restoration of BNIP3 expression in pancreatic cancer cells in vitro, caused loss of ΔΨm, increase in ROS production, and apoptosis induction. The opposite effect was observed in pancreatic cancer cells, following BNIP3 silencing by RNAi. The absence of BNIP3 expression in pancreatic cancer cells was related to gene methylation that suppressed binding of HIF-1α to the BNIP3 promoter, whereas 5-Aza-2'-deoxycytidine (Aza-dC) treatment restored BNIP3 expression and sensitized pancreatic cancer cells to BNIP3-induced apoptosis. The findings indicated that BNIP3 was significantly downregulated in pancreatic cancer resulting in reduced apoptosis induction. Silencing of BNIP3 expression was associated with methylation of the hypoxia-responsive element (HRE) site that in turn inhibited the binding of HIF-1α to the BNIP3 promoter. The data suggest that BNIP3 reactivation is a potential target for therapeutic intervention against pancreatic cancer.
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