PADI2 gene confers susceptibility to breast cancer and plays tumorigenic role via ACSL4, BINC3 and CA9 signaling

Huifeng Wang; Bing Xu; Xiaoqian Zhang; Yabing Zheng; Yan Zhao; Xiaotian Chang

doi:10.1186/s12935-016-0335-0

PADI2 gene confers susceptibility to breast cancer and plays tumorigenic role via ACSL4, BINC3 and CA9 signaling

Cancer Cell Int. 2016 Jul 29:16:61. doi: 10.1186/s12935-016-0335-0. eCollection 2016.

Authors

Huifeng Wang¹, Bing Xu², Xiaoqian Zhang³, Yabing Zheng², Yan Zhao², Xiaotian Chang²

Affiliations

¹ Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jingshi Road 16766, Jinan, 250014 Shandong People's Republic of China ; Taian City Central Hospital, Longtan Road 29, Taian, 271000 Shandong People's Republic of China.
² Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jingshi Road 16766, Jinan, 250014 Shandong People's Republic of China.
³ Clinical Laboratory of PKUCare Luzhong Hospital, Taigong Road 65, Zibo, 250400 Shandong People's Republic of China.

Abstract

Background: Peptidylarginine deiminase (PAD) post-translationally converts arginine residues to citrulline residues. Recent studies have suggested that PADI2 (PAD isoform 2), a member of the PAD family, is involved in the tumorigenic process of some tumors, especially breast cancer. However, little is known about the mechanisms of PADI2 in tumorigenesis. This study aimed to elucidate the tumorigenic role and regulatory pathway of PADI2 in breast tumors.

Methods: The Sequenom MassARRAY and TaqMan genotyping methods were used to investigate the correlation between PADI2 gene SNPs and various tumor risks. PCR array analyses, including cancer pathway finder and signal transduction PCR arrays, were performed to investigate the tumorigenic pathway of PADI2 in the MCF-7 breast cancer cell line following treatment with anti-PADI2 siRNA. Cell proliferation, apoptosis and transwell migration assays were performed to observe the effect of PADI2 in MCF-7 cells treated with anti-PADI2 siRNA.

Results: Both Sequenom MassARRAY and TaqMan genotyping assays demonstrated that SNP rs10788656 in the PADI2 gene was significantly associated with breast cancer. PCR arrays indicated that inhibiting PADI2 expression significantly increased expression of CA9 and decreased expression of ACSL4 and BIRC3 in MCF-7 cells, which was verified using real-time PCR. Inhibiting PADI2 expression also significantly decreased the migration ability of MCF-7 cells but did not affect cell proliferation or apoptosis.

Conclusions: The PADI2 gene confers susceptibility to breast cancer. PADI2 expression contributes to abnormal migration of breast tumor cells. PADI2 affects tumorigenesis in breast tumor cells by regulating the expression of ACSL4, BINC3 and CA9, which are known to promote abnormal lipid metabolism and cell invasion of tumors.

Keywords: ACSL4 (long-chain fatty acyl-CoA synthetase 4); BIRC3 (baculoviral IAP repeat containing 3); CA9 (carbonic anhydrase IX); Citrullination; PADI2 (peptidylarginine deiminase isoform 2); Peptidylarginine deiminase (PAD).