title: SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma.
abstract: Nasopharyngeal 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.
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: H L
authors.initials: HL
authors.lastname: Lung
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: O Y
authors.initials: OY
authors.lastname: Man
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: M C
authors.initials: MC
authors.lastname: Yeung
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: J M Y
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: A K L
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: E W L
authors.initials: EW
authors.lastname: Law
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: W H
authors.initials: WH
authors.lastname: Shuen
authors.affiliation: 1] Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China.
authors.forename: E
authors.initials: E
authors.lastname: Tung
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: S H K
authors.initials: SH
authors.lastname: Chan
authors.affiliation: Genome Institute of Singapore, Biomedical Sciences Institutes, Singapore.
authors.forename: D K
authors.initials: DK
authors.lastname: Bangarusamy
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Kan
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Phoon
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: K C
authors.initials: KC
authors.lastname: Chan
authors.affiliation: 1] Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China [3] Comprehensive Oncology Centre, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong (SAR), People's Republic of China.
authors.forename: D
authors.initials: D
authors.lastname: Chua
authors.affiliation: 1] Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China.
authors.forename: D L
authors.initials: DL
authors.lastname: Kwong
authors.affiliation: 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China [2] Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong (SAR), People's Republic of China [3] Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China.
authors.forename: A W M
authors.initials: AW
authors.lastname: Lee
authors.affiliation: Cancer Center, Zhongshan City Hospital, Zhongshan, People's Republic of China.
authors.forename: M F
authors.initials: MF
authors.lastname: Ji
authors.affiliation: 1] Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China.
authors.forename: M L
authors.initials: ML
authors.lastname: Lung
mesh_terms: D000483:Alleles; D017209:Apoptosis; D002277:Carcinoma; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D042783:Endothelial Cells; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D000685:Serum Amyloid A Protein / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C521404:SAA1 protein, human; D000685:Serum Amyloid A Protein; D025521:Tumor Suppressor Proteins