title: Deletion of phospholipase A2 group IVc induces apoptosis in rat mammary tumour cells by the nuclear factor-κB/lipocalin 2 pathway.
abstract: Although some forms of phospholipase A2, the initiator of the arachidonic acid cascade, contribute to carcinogenesis in many organs, the contribution of phospholipase A2 group IVc (Pla2g4c) remains to be clarified and the function of the enzyme in cancer development is unknown. The Hirosaki hairless rat (HHR), a mutant rat strain with autosomal recessive inheritance, derived spontaneously from the Sprague-Dawley rat (SDR). The HHRs showed a lower incidence and much smaller volume of mammary tumours induced by 7,12-dimethylbenz[a]anthracene, and a markedly increased number of TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling)-positive apoptotic cells was detected. Array comparative genomic hybridization and PCR analyses revealed the deletion of 50-kb genomic DNA on 1q21, including Pla2g4c, in HHRs. The Pla2g4c gene was expressed in the ductal carcinoma cells and myoepithelial cells in SDRs, but not in HHRs. The direct involvement of Pla2g4c in the prevention of cell death was demonstrated through the inhibition of its expression in rat mammary tumour RMT-1 cells using siRNA. This treatment also induced expression of lipocalin 2 (Lcn2) and other NF-κB (nuclear factor κB)-related genes. siRNA-induced apoptosis was inhibited by Lcn2 repression or NF-κB inhibitors. This is the first report on Pla2g4c gene-deficient rats and their low susceptibility to mammary carcinogenesis by enhancing NF-κB/Lcn2-induced apoptosis.
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan Department of Biomedical Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki 036-8564, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nanashima
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan tsuchida@hirosaki-u.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsuchida
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D054772:Rats, Hairless; D017207:Rats, Sprague-Dawley
chemical_list: C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D054513:Group IV Phospholipases A2
keywords: apoptosis; homologous recombination; lipocalin 2; mammary cancer; phospholipase A2