CypA, a gene downstream of HIF-1α, promotes the development of PDAC

Huan Zhang; Jing Chen; Fenghua Liu; Chuntao Gao; Xiuchao Wang; Tiansuo Zhao; Jingcheng Liu; Song Gao; Xiao Zhao; He Ren; Jihui Hao

doi:10.1371/journal.pone.0092824

CypA, a gene downstream of HIF-1α, promotes the development of PDAC

PLoS One. 2014 Mar 24;9(3):e92824. doi: 10.1371/journal.pone.0092824. eCollection 2014.

Authors

Huan Zhang¹, Jing Chen¹, Fenghua Liu¹, Chuntao Gao¹, Xiuchao Wang¹, Tiansuo Zhao¹, Jingcheng Liu¹, Song Gao¹, Xiao Zhao¹, He Ren¹, Jihui Hao¹

Affiliation

¹ National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a highly important transcription factor involved in cell metabolism. HIF-1α promotes glycolysis and inhibits of mitochondrial respiration in pancreatic ductal adenocarcinoma (PDAC). In response to tumor hypoxia, cyclophilin A (CypA) is over-expressed in various cancer types, and is associated with cell apoptosis, tumor invasion, metastasis, and chemoresistance in PDAC. In this study, we showed that both HIF-1α and CypA expression were significantly associated with lymph node metastasis and tumor stage. The expression of CypA was correlated with HIF-1α. Moreover, the mRNA and protein expression of CypA markedly decreased or increased following the suppression or over-expression of HIF-1α in vitro. Chromatin immunoprecipitation analysis showed that HIF-1α could directly bind to the hypoxia response element (HRE) in the CypA promoter regions and regulated CypA expression. Consistent with other studies, HIF-1α and CypA promoted PDAC cell proliferation and invasion, and suppressed apoptosis in vitro. Furthermore, we proved the combination effect of 2-methoxyestradiol and cyclosporin A both in vitro and in vivo. These results suggested that,CypA, a gene downstream of HIF-1α, could promote the development of PDAC. Thus, CypA might serve as a potential therapeutic target for PDAC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism*
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Cell Proliferation
Cyclophilin A / genetics
Cyclophilin A / metabolism*
Female
Gene Expression Regulation, Neoplastic / genetics
Genes, Neoplasm*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Male
Mice
Mice, SCID
Middle Aged
Neoplasm Invasiveness
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Neoplasm Proteins
RNA, Messenger
RNA, Neoplasm
Cyclophilin A

Grants and funding

Funding: National Natural Science Foundation of China (Grant No. 81302082, 81272685, 31301151, 81172355); Doctoral Fund of Ministry of Education of China (Grant No. 20101202110002; Key program of Natural Science Foundation of Tianjin (Grant No. 09JCZDJC17100, 11JCZDJC18400); major anticancer Technologies R & D Program of Tianjin (Grant No. 12ZCDZSY16700); project of Tianjin Educational Commission (Grant No. 20100123). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.