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

Oncogene volume 34, pages 878–889 (2015)Cite this article

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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.

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Abbreviations

ECM:

extracellular matrix

MCH:

microcell hybrid

NPC:

nasopharyngeal carcinoma

SAA1:

serum amyloid A1

TSG:

tumor suppressor gene

TS:

tumor segregant.

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Acknowledgements

We acknowledge the AoE NPC Tissue Bank for providing the NPC specimens and the NPC TMA. We thank the Hong Kong Red Cross for providing us the blood from healthy individuals. We also thank Dr Edison Tak-Bun Liu for their microarray support in the Genome Institute of Singapore (GIS); Dr Sai Wah Tsao for providing us the immortalized cell lines; Dr John M Nicholls for the TMA analysis and Dr Pui Man Chiu for her help in constructing the NPC TMA and SAA immunohistochemistry staining; Dr Didier Trono for the supply of the lentiviral vectors, pWPI, pMD2.G and psPAX2. We thank Dr David Root for the supply of the lentihair pLKO.1-TRC cloning vector and Dr David Sabatini for the pLKO.1-scramble shRNA construct. This work was supported by the General Research Fund (HKU772309 to HLL) of the Research Grants Council of the Hong Kong Special Administrative Region.

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Author notes

  1. D K Bangarusamy

    Present address: 8Current address: SciGenom Labs , Plot 43A, SDF 3rd Floor CSEZ, Kakkanad, Cochin, Kerala, 682037, India,

Authors and Affiliations

  1. Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China

    H L Lung, O Y Man, M C Yeung, J M Y Ko, A K L Cheung, E W L Law, Z Yu, W H Shuen, E Tung, S H K Chan, Y Cheng, X Yang, R Kan, Y Phoon, K C Chan, D Chua, D L Kwong & M L Lung

  2. Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China

    E Tung, D Chua, D L Kwong, A W M Lee & M L Lung

  3. Genome Institute of Singapore, Biomedical Sciences Institutes, Singapore

    D K Bangarusamy

  4. Comprehensive Oncology Centre, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong (SAR), People's Republic of China

    D Chua

  5. Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong (SAR), People's Republic of China

    A W M Lee

  6. Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China,

    A W M Lee

  7. Cancer Center, Zhongshan City Hospital, Zhongshan, People's Republic of China

    M F Ji

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Lung, H., Man, O., Yeung, M. et al. SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma. Oncogene 34, 878–889 (2015). https://doi.org/10.1038/onc.2014.12

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