{"id":{"repo_id":"cagliari","oai_identifier":"oai:iris.unica.it:11584/266367"},"canonical_url":"https://search.dev.ndltd.org/etd/cagliari/oai:iris.unica.it:11584/266367","repository":{"repo_id":"cagliari","name":"Università di Cagliari","base_url":"https://iris.unica.it/oai/request"},"display":{"title":"Role of Hydroxy acid oxidase 2 (Hao2) in hepatocellular carcinoma","abstract":"Background: Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes. Although it is unclear whether 2-hydroxy acid oxidases contribute to a general mechanism of fatty acid α-oxidation, these enzymes are capable of oxidizing a broad range of 2-hydroxy acids, ranging from glycolate to long chain 2-hydroxy fatty acids, such as 2-hydroxypalmitate, to 2-keto acids; this reaction results in hydrogen peroxide (H2O2) formation at the expense of molecular oxygen. Aim: Since no data concerning Hao2, a member of this family, and cancer are available in the literature, we analyzed the expression of this enzyme in mouse, rat and human hepatocellular carcinoma (HCC). Results: Our microarray analysis, performed in the liver of rats subjected to the Resistant Hepatocyte (R-H) model, revealed that Hao2 was among the most down-regulated genes in HCCs developed, 14 months after initiation with a single dose of the hepatocarcinogen Diethylnitrosamine (DENA). Next, we investigated whether Hao2 down-regulation is an early event during liver carcinogenesis; to this aim, we analyzed the expression of Hao2 by qRT-PCR in preneoplastic lesions and HCCs generated 10 weeks, and 14 months after initiation, respectively. Interestingly, qRT-PCR showed down-regulation of Hao2 already in rat early preneoplastic lesions, especially in those positive for the putative progenitor cell marker KRT-19, considered to be the precursor of HCC in this model of hepatocarcinogenesis. Western blot analysis showed Hao2 down-regulation also at protein level. To determine whether this down-regulation is a general phenomenon in liver tumorigenesis or is specific only for rat liver, we analyze the expression of Hao2 in a chemically-induced mouse model of hepatocarcinogenesis, consisting of a single injection of DENA followed by treatment with TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)] benzene), a ligand of the nuclear receptor CAR (Constitutive androstane receptor), that causes massive hepatomegaly and then HCC. Notably, similar to what found in rat HCC, Hao2 was strongly down-regulated also in TCP-induced mouse HCC. Finally, we investigated the expression levels of Hao2 in two distinct series of human HCCs. Interestingly, we found a strong down-regulation of Hao2 gene in human HCCs when compared to both normal and cirrhotic peri-tumoral liver. Furthermore, the levels of Hao2 were inversely correlated with time of recurrence, overall survival and occurrence of metastases. Conclusions: These results describe, for the first time, that Hao2 deregulation is severely impaired in HCCs generated in three different species and by different etiological agents. They also demonstrate that down-regulation of Hao2 is a very early event in the development of HCC, and may represent a useful diagnostic tool and a marker of poor prognosis.","abstract_html":"Background: Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes. Although it is unclear whether 2-hydroxy acid oxidases contribute to a general mechanism of fatty acid α-oxidation, these enzymes are capable of oxidizing a broad range of 2-hydroxy acids, ranging from glycolate to long chain 2-hydroxy fatty acids, such as 2-hydroxypalmitate, to 2-keto acids; this reaction results in hydrogen peroxide (H2O2) formation at the expense of molecular oxygen. Aim: Since no data concerning Hao2, a member of this family, and cancer are available in the literature, we analyzed the expression of this enzyme in mouse, rat and human hepatocellular carcinoma (HCC). Results: Our microarray analysis, performed in the liver of rats subjected to the Resistant Hepatocyte (R-H) model, revealed that Hao2 was among the most down-regulated genes in HCCs developed, 14 months after initiation with a single dose of the hepatocarcinogen Diethylnitrosamine (DENA). Next, we investigated whether Hao2 down-regulation is an early event during liver carcinogenesis; to this aim, we analyzed the expression of Hao2 by qRT-PCR in preneoplastic lesions and HCCs generated 10 weeks, and 14 months after initiation, respectively. Interestingly, qRT-PCR showed down-regulation of Hao2 already in rat early preneoplastic lesions, especially in those positive for the putative progenitor cell marker KRT-19, considered to be the precursor of HCC in this model of hepatocarcinogenesis. Western blot analysis showed Hao2 down-regulation also at protein level. To determine whether this down-regulation is a general phenomenon in liver tumorigenesis or is specific only for rat liver, we analyze the expression of Hao2 in a chemically-induced mouse model of hepatocarcinogenesis, consisting of a single injection of DENA followed by treatment with TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)] benzene), a ligand of the nuclear receptor CAR (Constitutive androstane receptor), that causes massive hepatomegaly and then HCC. Notably, similar to what found in rat HCC, Hao2 was strongly down-regulated also in TCP-induced mouse HCC. Finally, we investigated the expression levels of Hao2 in two distinct series of human HCCs. Interestingly, we found a strong down-regulation of Hao2 gene in human HCCs when compared to both normal and cirrhotic peri-tumoral liver. Furthermore, the levels of Hao2 were inversely correlated with time of recurrence, overall survival and occurrence of metastases. Conclusions: These results describe, for the first time, that Hao2 deregulation is severely impaired in HCCs generated in three different species and by different etiological agents. They also demonstrate that down-regulation of Hao2 is a very early event in the development of HCC, and may represent a useful diagnostic tool and a marker of poor prognosis.","abstract_has_math":false,"creators":["MATTU, SANDRA"],"institution":"Università degli Studi di Cagliari","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-05-06","date_published":"2015-05-06","updated_at":"2026-07-24T01:30:01Z","subjects":["Hydroxy acid oxidase 2 (Hao2)","carcinoma epatocellulare","fegato","hepatocellular carcinoma","idrossiacidoossidasi-2 (Hao2)","liver","Settore MED/04 - Patologia Generale"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess","license:Non specificato"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/11584/266367","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["MATTU, SANDRA"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015-05-06"]},{"key":"dc:publisher","label":"Institution","values":["Università degli Studi di Cagliari"]},{"key":"dc:relation","label":"Dc Relation","values":["numberofpages:73"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Hydroxy acid oxidase 2 (Hao2)","carcinoma epatocellulare","fegato","hepatocellular carcinoma","idrossiacidoossidasi-2 (Hao2)","liver","Settore MED/04 - Patologia Generale"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess","license:Non specificato"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/11584/266367"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Background: Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes. Although it is unclear whether 2-hydroxy acid oxidases contribute to a general mechanism of fatty acid α-oxidation, these enzymes are capable of oxidizing a broad range of 2-hydroxy acids, ranging from glycolate to long chain 2-hydroxy fatty acids, such as 2-hydroxypalmitate, to 2-keto acids; this reaction results in hydrogen peroxide (H2O2) formation at the expense of molecular oxygen. Aim: Since no data concerning Hao2, a member of this family, and cancer are available in the literature, we analyzed the expression of this enzyme in mouse, rat and human hepatocellular carcinoma (HCC). Results: Our microarray analysis, performed in the liver of rats subjected to the Resistant Hepatocyte (R-H) model, revealed that Hao2 was among the most down-regulated genes in HCCs developed, 14 months after initiation with a single dose of the hepatocarcinogen Diethylnitrosamine (DENA). Next, we investigated whether Hao2 down-regulation is an early event during liver carcinogenesis; to this aim, we analyzed the expression of Hao2 by qRT-PCR in preneoplastic lesions and HCCs generated 10 weeks, and 14 months after initiation, respectively. Interestingly, qRT-PCR showed down-regulation of Hao2 already in rat early preneoplastic lesions, especially in those positive for the putative progenitor cell marker KRT-19, considered to be the precursor of HCC in this model of hepatocarcinogenesis. Western blot analysis showed Hao2 down-regulation also at protein level. To determine whether this down-regulation is a general phenomenon in liver tumorigenesis or is specific only for rat liver, we analyze the expression of Hao2 in a chemically-induced mouse model of hepatocarcinogenesis, consisting of a single injection of DENA followed by treatment with TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)] benzene), a ligand of the nuclear receptor CAR (Constitutive androstane receptor), that causes massive hepatomegaly and then HCC. Notably, similar to what found in rat HCC, Hao2 was strongly down-regulated also in TCP-induced mouse HCC. Finally, we investigated the expression levels of Hao2 in two distinct series of human HCCs. Interestingly, we found a strong down-regulation of Hao2 gene in human HCCs when compared to both normal and cirrhotic peri-tumoral liver. Furthermore, the levels of Hao2 were inversely correlated with time of recurrence, overall survival and occurrence of metastases. Conclusions: These results describe, for the first time, that Hao2 deregulation is severely impaired in HCCs generated in three different species and by different etiological agents. They also demonstrate that down-regulation of Hao2 is a very early event in the development of HCC, and may represent a useful diagnostic tool and a marker of poor prognosis."]},{"key":"dc:title","label":"Title","values":["Role of Hydroxy acid oxidase 2 (Hao2) in hepatocellular carcinoma"]}]}],"canonical_facts":{"dc:creator":["MATTU, SANDRA"],"dc:date":["2015-05-06"],"dc:description":["Background: Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes. Although it is unclear whether 2-hydroxy acid oxidases contribute to a general mechanism of fatty acid α-oxidation, these enzymes are capable of oxidizing a broad range of 2-hydroxy acids, ranging from glycolate to long chain 2-hydroxy fatty acids, such as 2-hydroxypalmitate, to 2-keto acids; this reaction results in hydrogen peroxide (H2O2) formation at the expense of molecular oxygen. Aim: Since no data concerning Hao2, a member of this family, and cancer are available in the literature, we analyzed the expression of this enzyme in mouse, rat and human hepatocellular carcinoma (HCC). Results: Our microarray analysis, performed in the liver of rats subjected to the Resistant Hepatocyte (R-H) model, revealed that Hao2 was among the most down-regulated genes in HCCs developed, 14 months after initiation with a single dose of the hepatocarcinogen Diethylnitrosamine (DENA). Next, we investigated whether Hao2 down-regulation is an early event during liver carcinogenesis; to this aim, we analyzed the expression of Hao2 by qRT-PCR in preneoplastic lesions and HCCs generated 10 weeks, and 14 months after initiation, respectively. Interestingly, qRT-PCR showed down-regulation of Hao2 already in rat early preneoplastic lesions, especially in those positive for the putative progenitor cell marker KRT-19, considered to be the precursor of HCC in this model of hepatocarcinogenesis. Western blot analysis showed Hao2 down-regulation also at protein level. To determine whether this down-regulation is a general phenomenon in liver tumorigenesis or is specific only for rat liver, we analyze the expression of Hao2 in a chemically-induced mouse model of hepatocarcinogenesis, consisting of a single injection of DENA followed by treatment with TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)] benzene), a ligand of the nuclear receptor CAR (Constitutive androstane receptor), that causes massive hepatomegaly and then HCC. Notably, similar to what found in rat HCC, Hao2 was strongly down-regulated also in TCP-induced mouse HCC. Finally, we investigated the expression levels of Hao2 in two distinct series of human HCCs. Interestingly, we found a strong down-regulation of Hao2 gene in human HCCs when compared to both normal and cirrhotic peri-tumoral liver. Furthermore, the levels of Hao2 were inversely correlated with time of recurrence, overall survival and occurrence of metastases. Conclusions: These results describe, for the first time, that Hao2 deregulation is severely impaired in HCCs generated in three different species and by different etiological agents. They also demonstrate that down-regulation of Hao2 is a very early event in the development of HCC, and may represent a useful diagnostic tool and a marker of poor prognosis."],"dc:identifier":["http://hdl.handle.net/11584/266367"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Cagliari"],"dc:relation":["numberofpages:73"],"dc:rights":["info:eu-repo/semantics/openAccess","license:Non specificato"],"dc:subject":["Hydroxy acid oxidase 2 (Hao2)","carcinoma epatocellulare","fegato","hepatocellular carcinoma","idrossiacidoossidasi-2 (Hao2)","liver","Settore MED/04 - Patologia Generale"],"dc:title":["Role of Hydroxy acid oxidase 2 (Hao2) in hepatocellular carcinoma"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-24T01:30:01Z"}