title: Ptgr1 expression is regulated by NRF2 in rat hepatocarcinogenesis and promotes cell proliferation and resistance to oxidative stress.
abstract: Prostaglandin reductase-1 (Ptgr1) is an alkenal/one oxidoreductase that is involved in the catabolism of eicosanoids and lipid peroxidation such as 4-hydroxynonenal (4-HNE). Recently, we reported that Ptgr1 is overexpressed in human clinical and experimentally induced samples of hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated and its role in carcinogenesis are not yet known. Here, we studied parameters associated with antioxidant responses and the mechanisms underlying the induction of Ptgr1 expression by the activation of Nuclear Factor (erythroid-derived-2)-like-2 (NRF2). For these experiments, we used two protocols of induced hepatocarcinogenesis in rats. Furthermore, we determined the effect of PTGR1 on cell proliferation and resistance to oxidative stress in cell cultures of the epithelial liver cell line, C9. Ptgr1 was overexpressed during the early phase in altered hepatocyte foci, and this high level of expression was maintained in persistent nodules until tumors developed. Ptgr1 expression was regulated by NRF2, which bound to an antioxidant response element at -653bp in the rat Ptgr1 gene. The activation of NRF2 induced the activation of an antioxidant response that included effects on proteins such as glutamate-cysteine ligase, catalytic subunit, NAD(P)H dehydrogenase quinone-1 (NQO1) and glutathione-S-transferase-P (GSTP1). These effects may have produced a reduced status that was associated with a high proliferation rate in experimental tumors. Indeed, when Ptgr1 was stably expressed, we observed a reduction in the time required for proliferation and a protective effect against hydrogen peroxide- and 4-HNE-induced cell death. These data were consistent with data showing colocalization between PTGR1 and 4-HNE protein adducts in liver nodules. These findings suggest that Ptgr1 and antioxidant responses act as a metabolic adaptation and could contribute to proliferation and cell-death evasion in liver tumor cells. Furthermore, these data indicate that Ptgr1 could be used to design early diagnostic tools or targeted therapies for HCC.
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Rodríguez
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico; Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico.
authors.forename: Julia Esperanza
authors.initials: JE
authors.lastname: Torres-Mena
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico.
authors.forename: Valeria
authors.initials: V
authors.lastname: Quintanar-Jurado
authors.affiliation: Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico.
authors.forename: Victoria
authors.initials: V
authors.lastname: Chagoya-Hazas
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico.
authors.forename: Emilio
authors.initials: E
authors.lastname: Rojas Del Castillo
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Pozo Yauner
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico.
authors.forename: Saul
authors.initials: S
authors.lastname: Villa-Treviño
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico. Electronic address: jiperez@inmegen.gob.mx.
authors.forename: Julio Isael
authors.initials: JI
authors.lastname: Pérez-Carreón
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000429:Alcohol Oxidoreductases; C082646:leukotriene B4 12-hydroxydehydrogenase
keywords: 4-hydroxynonenal; Antioxidant response; Hepatocellular carcinoma; Oxidative stress; Redox balance