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Article: Allele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma

TitleAllele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma
Authors
Issue Date2014
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2014, v. 146 n. 4, p. 1084-1096.e5 How to Cite?
AbstractBACKGROUND and AIMS: Although there are a few highly penetrant mutations that are linked directly to cancer initiation, more less-penetrant susceptibility alleles have been associated with cancer risk and progression. We used RNA sequence analysis to search for genetic variations associated with pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed 400 paired HCC and adjacent nontumor tissues, along with clinical information, from patients who underwent surgery at Sun Yat-Sen University in Guangzhou, China. Total RNA was extracted from tissues and sequenced, and variations with allele imbalance were identified. Effects of variants on cell functions were investigated in HCC cell lines and tumor xenografts in mice. Variants were associated with patient outcomes. RESULTS: We found a high proportion of allele imbalance in genes related to cellular stress. A nucleotide variation in the Oxidative Stress-Induced Growth Inhibitor 1 (OSGIN1) gene (nt 1494: G-A) resulted in an amino acid substitution (codon 438: Arg-His). The variant form of OSGIN1 was specifically retained in the tumor tissues. Functional assays showed that the common form of OSGIN1 functioned as a tumor suppressor, sensitizing HCC cells to chemotherapeutic agents by inducing apoptosis. However, the variant form of OSGIN1 was less effective. It appeared to affect the translocation of OSGIN1 from the nucleus to mitochondria, which is important for its apoptotic function. The expression pattern and localization of OSGIN1 was altered in HCC specimens, compared with adjacent liver tissue. Levels of OSGIN1 messenger RNA were reduced in 24.7% of HCC specimens, and down-regulation was associated with shorter overall and disease-free survival times of patients. Patients with the OSGIN1 1494A variant had the shortest mean survival time (32.68 mo) among patient subgroups, and their tumor samples had the lowest apoptotic index. CONCLUSIONS: We identified OSGIN1 as a tumor suppressor that is down-regulated or altered in human HCCs. Variants of OSGIN1 detected in HCC samples reduce apoptosis and are associated with shorter survival times of patients.
Persistent Identifierhttp://hdl.handle.net/10722/198472
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, M-
dc.contributor.authorLi, Y-
dc.contributor.authorChen, L-
dc.contributor.authorChan, THM-
dc.contributor.authorSONG, Y-
dc.contributor.authorFu, L-
dc.contributor.authorZeng, TT-
dc.contributor.authorDai, YD-
dc.contributor.authorZhu, YH-
dc.contributor.authorLi, Y-
dc.contributor.authorCHEN, J-
dc.contributor.authorYuan, YF-
dc.contributor.authorGuan, X-
dc.date.accessioned2014-07-07T07:08:13Z-
dc.date.available2014-07-07T07:08:13Z-
dc.date.issued2014-
dc.identifier.citationGastroenterology, 2014, v. 146 n. 4, p. 1084-1096.e5-
dc.identifier.issn0016-5085-
dc.identifier.urihttp://hdl.handle.net/10722/198472-
dc.description.abstractBACKGROUND and AIMS: Although there are a few highly penetrant mutations that are linked directly to cancer initiation, more less-penetrant susceptibility alleles have been associated with cancer risk and progression. We used RNA sequence analysis to search for genetic variations associated with pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed 400 paired HCC and adjacent nontumor tissues, along with clinical information, from patients who underwent surgery at Sun Yat-Sen University in Guangzhou, China. Total RNA was extracted from tissues and sequenced, and variations with allele imbalance were identified. Effects of variants on cell functions were investigated in HCC cell lines and tumor xenografts in mice. Variants were associated with patient outcomes. RESULTS: We found a high proportion of allele imbalance in genes related to cellular stress. A nucleotide variation in the Oxidative Stress-Induced Growth Inhibitor 1 (OSGIN1) gene (nt 1494: G-A) resulted in an amino acid substitution (codon 438: Arg-His). The variant form of OSGIN1 was specifically retained in the tumor tissues. Functional assays showed that the common form of OSGIN1 functioned as a tumor suppressor, sensitizing HCC cells to chemotherapeutic agents by inducing apoptosis. However, the variant form of OSGIN1 was less effective. It appeared to affect the translocation of OSGIN1 from the nucleus to mitochondria, which is important for its apoptotic function. The expression pattern and localization of OSGIN1 was altered in HCC specimens, compared with adjacent liver tissue. Levels of OSGIN1 messenger RNA were reduced in 24.7% of HCC specimens, and down-regulation was associated with shorter overall and disease-free survival times of patients. Patients with the OSGIN1 1494A variant had the shortest mean survival time (32.68 mo) among patient subgroups, and their tumor samples had the lowest apoptotic index. CONCLUSIONS: We identified OSGIN1 as a tumor suppressor that is down-regulated or altered in human HCCs. Variants of OSGIN1 detected in HCC samples reduce apoptosis and are associated with shorter survival times of patients.-
dc.languageeng-
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro-
dc.relation.ispartofGastroenterology-
dc.rights© <year>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/-
dc.subject.meshAllelic Imbalance-
dc.subject.meshCarcinoma, Hepatocellular - genetics - metabolism - mortality - pathology - therapy-
dc.subject.meshGenes, Tumor Suppressor-
dc.subject.meshLiver Neoplasms - genetics - metabolism - mortality - pathology - therapy-
dc.subject.meshProteins - genetics - metabolism-
dc.titleAllele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailLiu, M: liuming@hku.hk-
dc.identifier.emailLi, Y: vikkiyan@hku.hk-
dc.identifier.emailChen, L: pollyllc@hku.hk-
dc.identifier.emailChan, THM: chantim@hkucc.hku.hk-
dc.identifier.emailFu, L: gracefu@graduate.hku.hk-
dc.identifier.emailGuan, X: xyguan@hkucc.hku.hk-
dc.identifier.authorityFu, L=rp01435-
dc.identifier.authorityGuan, X=rp00454-
dc.identifier.doi10.1053/j.gastro.2013.12.041-
dc.identifier.pmid24417816-
dc.identifier.scopuseid_2-s2.0-84896454039-
dc.identifier.hkuros229765-
dc.identifier.volume146-
dc.identifier.issue4-
dc.identifier.spage1084-
dc.identifier.epage1096.e5-
dc.identifier.isiWOS:000333254500037-
dc.publisher.placeUnited States-

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