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Article: SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma

TitleSAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma
Authors
Issue Date2015
Citation
Oncogene, 2015, v. 34, p. 878-889 How to Cite?
AbstractNasopharyngeal carcinoma (NPC) is a cancer that occurs in high frequency in Southern China. A previous functional complementation approach and the subsequent cDNA microarray analysis have identified that serum amyloid A1 (SAA1) is an NPC candidate tumor suppressor gene. SAA1 belongs to a family of acute-phase proteins that are encoded by five polymorphic coding alleles. The SAA1 genotyping results showed that only three SAA1 isoforms (SAA1.1, 1.3 and 1.5) were observed in both Hong Kong NPC patients and healthy individuals. This study aims to determine the functional role of SAA1 polymorphisms in tumor progression and to investigate the relationship between SAA1 polymorphisms and NPC risk. Indeed, we have shown that restoration of SAA1.1 and 1.3 in the SAA1-deficient NPC cell lines could suppress tumor formation and angiogenesis in vitro and in vivo. The secreted SAA1.1 and SAA1.3 proteins can block cell adhesion and induce apoptosis in the vascular endothelial cells. In contrast, the SAA1.5 cannot induce apoptosis or inhibit angiogenesis because of its weaker binding affinity to αVβ3 integrin. This can explain why SAA1.5 has no tumor-suppressive effects. Furthermore, the NPC tumors with this particular SAA1.5/1.5 genotype showed higher levels of SAA1 gene expression, and SAA1.1 and 1.3 alleles were preferentially inactivated in tumor tissues that were examined. These findings further strengthen the conclusion for the defective function of SAA1.5 in suppression of tumor formation and angiogenesis. Interestingly, the frequency of the SAA1.5/1.5 genotype in NPC patients was ~2-fold higher than in the healthy individuals (P=0.00128, odds ratio=2.28), which indicates that this SAA1 genotype is significantly associated with a higher NPC risk. Collectively, this homozygous SAA1.5/1.5 genotype appears to be a recessive susceptibility gene, which has lost the antiangiogenic function, whereas SAA1.1 and SAA1.3 are the dominant alleles of the tumor suppressor phenotype.
Persistent Identifierhttp://hdl.handle.net/10722/198009

 

DC FieldValueLanguage
dc.contributor.authorLung, HLen_US
dc.contributor.authorMan, OYen_US
dc.contributor.authorYeung, MCen_US
dc.contributor.authorKo, JMYen_US
dc.contributor.authorCheung, AKLen_US
dc.contributor.authorLaw, WLen_US
dc.contributor.authorYu, Zen_US
dc.contributor.authorShuen, WHen_US
dc.contributor.authorTung, Een_US
dc.contributor.authorChan, SHKen_US
dc.date.accessioned2014-06-25T02:39:49Z-
dc.date.available2014-06-25T02:39:49Z-
dc.date.issued2015en_US
dc.identifier.citationOncogene, 2015, v. 34, p. 878-889en_US
dc.identifier.urihttp://hdl.handle.net/10722/198009-
dc.description.abstractNasopharyngeal carcinoma (NPC) is a cancer that occurs in high frequency in Southern China. A previous functional complementation approach and the subsequent cDNA microarray analysis have identified that serum amyloid A1 (SAA1) is an NPC candidate tumor suppressor gene. SAA1 belongs to a family of acute-phase proteins that are encoded by five polymorphic coding alleles. The SAA1 genotyping results showed that only three SAA1 isoforms (SAA1.1, 1.3 and 1.5) were observed in both Hong Kong NPC patients and healthy individuals. This study aims to determine the functional role of SAA1 polymorphisms in tumor progression and to investigate the relationship between SAA1 polymorphisms and NPC risk. Indeed, we have shown that restoration of SAA1.1 and 1.3 in the SAA1-deficient NPC cell lines could suppress tumor formation and angiogenesis in vitro and in vivo. The secreted SAA1.1 and SAA1.3 proteins can block cell adhesion and induce apoptosis in the vascular endothelial cells. In contrast, the SAA1.5 cannot induce apoptosis or inhibit angiogenesis because of its weaker binding affinity to αVβ3 integrin. This can explain why SAA1.5 has no tumor-suppressive effects. Furthermore, the NPC tumors with this particular SAA1.5/1.5 genotype showed higher levels of SAA1 gene expression, and SAA1.1 and 1.3 alleles were preferentially inactivated in tumor tissues that were examined. These findings further strengthen the conclusion for the defective function of SAA1.5 in suppression of tumor formation and angiogenesis. Interestingly, the frequency of the SAA1.5/1.5 genotype in NPC patients was ~2-fold higher than in the healthy individuals (P=0.00128, odds ratio=2.28), which indicates that this SAA1 genotype is significantly associated with a higher NPC risk. Collectively, this homozygous SAA1.5/1.5 genotype appears to be a recessive susceptibility gene, which has lost the antiangiogenic function, whereas SAA1.1 and SAA1.3 are the dominant alleles of the tumor suppressor phenotype.-
dc.languageengen_US
dc.relation.ispartofOncogeneen_US
dc.titleSAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinomaen_US
dc.typeArticleen_US
dc.identifier.emailLung, HL: hllung2@hku.hken_US
dc.identifier.emailKo, JMY: joko@hku.hken_US
dc.identifier.emailCheung, AKL: arthurhk@hku.hken_US
dc.identifier.emailYu, Z: zvyu@hku.hken_US
dc.identifier.emailTung, E: elenat@hku.hken_US
dc.identifier.authorityLung, HL=rp00299en_US
dc.identifier.authorityCheung, AKL=rp01769en_US
dc.identifier.doi10.1038/onc.2014.12en_US
dc.identifier.scopuseid_2-s2.0-84895416688-
dc.identifier.hkuros227889-

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