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

Lung, Hong Lok; Man, On Ying; Yeung, Maximus C F; Ko, Josephine Mun Yee; Cheung, Arthur Kwok Leung; Law, Evan Wai Lok; Yu, Zhe; Shuen, Timothy Wai Ho; Tung, Edmund Kwok–Kwan; Chan, Stephen; Bangarusamy, Dhinoth Kumar; Cheng, Yue; Yang, Xin; Kan, Rebecca; Phoon, Yee Peng; Chan, Ka‐Kui; Chua, Dtt; Kwong, Dora L.W.; Lee, A W M; Ji, Mingfang; Lung, ML

doi:10.1038/onc.2014.12

Cited by 25 publications

(28 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings suggest that amino acid substitutions occurring at two positions in SAA1 are sufficient to alter its structure, leading to functional changes. During the course of this study, Lung et al reported that SAA1 polymorphisms are associated with variation in tumor-suppressive and angiogenic activities based on a study of nasopharyngeal carcinoma (Lung et al, 2014). This study not only established a functional association of the SAA1 allelic variation with a particular type of tumor, but also show that the ability of an SAA1 isoform to interact with the integrin αVβ3 directly correlates with its tumor-suppressive activity.…”

Section: Discussionmentioning

confidence: 95%

“…1A). Previous studies have shown that these SAA1 isoforms might contribute differently to chronic diseases such as amyloidosis (Buxbaum, 2006) and nasopharyngeal carcinoma (Lung et al, 2014). To understand the action mechanisms underlying the difference, we prepared recombinant proteins representing 3 different human SAA1 isoforms, using similarly prepared SAA2.2 for comparison.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, SAA1.1 has been considered a risk factor for amyloidosis in patients with RA (van der Hilst et al, 2008). Moreover, different alleles of SAA1 have been associated with other chronic diseases and cancer (Lung et al, 2014, Malle et al, 2009). However, the underlying mechanisms have not been fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Serum amyloid A1 isoforms display different efficacy at Toll-like receptor 2 and formyl peptide receptor 2

et al. 2014

View full text Add to dashboard Cite

Serum amyloid A (SAA) is a major acute-phase protein and a precursor of amyloid A, the deposit of which leads to amyloidosis. Different alleles exist in SAA1, a predominant form of the human SAA gene family. Emerging evidence has shown correlations between these alleles and diseases including familiar Mediterranean fever and amyloidosis. However, it remains unclear how the proteins encoded by these SAA1 alleles act differently. Here we report the characterization of proteins encoded by SAA1.1, SAA1.3 and SAA1.5, in comparison to that encoded by SAA2.2, for their preference of the SAA receptors including formyl peptide receptor 2 (FPR2) and Toll-like receptor 2 (TLR2). SAA1.1 was more efficacious than SAA1.3 and SAA1.5 but equally efficacious to SAA2.2 in calcium mobilization and chemotaxis assays, which measure the activation of the G protein-coupled FPR2. In agreement with this, SAA1.1 and SAA2.2 induced more robust phosphorylation of ERK than SAA1.3 and SAA1.5. Only small differences were observed between the SAA1 proteins tested and SAA2.2 in TLR2-dependent NF-κB luciferase reporter assay. In comparison, SAA1.3 was most effective in stimulating ERK and p38 MAPK phosphorylation. Using bone marrow-derived macrophages from C57BL/10ScN (Tlr4lps-del) mice, we examined the SAA isoforms for their induction of selected pro- and anti-inflammatory cytokines. SAA1.3 was most potent in the induction of TNFα and IL-1rn, whereas SAA1.5 induced robust IL-10 expression. These results show differences of the SAA1 isoforms in their selectivity for the SAA receptors, which may affect their roles in modulating inflammation and immunity.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Serum amyloid A1 isoforms display different efficacy at Toll-like receptor 2 and formyl peptide receptor 2

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Because of the close link between chronic inflammation and malignant transformation, SAA may affect tumorigenesis and tumor metastasis. A recent study has shown a close link between certain SAA1 allelic variants and the nasopharyngeal carcinoma, with some of these variants having anti-angiogenic and tumor-suppressive activities (Lung et al, 2014). Induced expression of matrix metalloproteases (Lee et al, 2005) and induction of angiogenesis (Mullan et al, 2006) may contribute to tumor metastasis and growth.…”

Section: Major Functions Of Human Saa1mentioning

confidence: 99%

“…A recent study links the high frequency of the SAA1.5/1.5 genotype in nasopharyngeal carcinoma patients with abrogated anti-angiogenic activity of the SAA1.5 protein (Lung et al, 2014). The study shows that SAA1.1 and SAA1.3 have higher affinity for the integrin αvβ3 than SAA1.5.…”

Section: Human Saa1 Polymorphism and Disease Dispositionmentioning

confidence: 99%

Serum amyloid A1: Structure, function and gene polymorphism

Sun

2016

Gene

159

134

View full text Add to dashboard Cite

Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1 – SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

show abstract

Serum amyloid A1 in combination with integrin αVβ3 increases glioblastoma cells mobility and progression

et al. 2018

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a highly malignant type of brain tumor found in humans. GBM cells reproduce quickly, and the median survival time for patients after therapy is approximately 1 year with a high relapse rate. Current therapies and diagnostic tools for GBM are limited; therefore, we searched for a more favorable therapeutic target or marker protein for both therapy and diagnosis. We used mass spectrometry (MS) analysis to identify GBM‐associated marker proteins from human plasma and GBM cell cultures. Additional plasma and 52 brain tissues obtained from patients with gliomas were used to validate the association rate of serum amyloid A1 (SAA1) in different grades of gliomas and its distribution in tumors. Microarray database analysis further validated the coefficient of SAA1 levels in gliomas. The cellular mechanisms of SAA1 in GBM proliferation and infiltration were investigated in vitro. We analyzed the correlation between SAA1 and patients' medication requirement to demonstrate the clinical effects of SAA1 in GBM. SAA1 was identified from MS analysis, and its level was revealed to be correlated with the disease grade, clinical severity, and survival rate of patients with gliomas. In vitro cultures, including GBM cells and normal astrocytes, revealed that SAA1 promotes cell migration and invasion through integrin αVβ3 to activate the Erk signaling pathway. Magnetic resonance imaging and tumor region‐specific microarray analysis identified a correlation between SAA1 and GBM cell infiltration in patients. In summary, our results demonstrate that SAA1 in combination with integrin αV and β3 can serve as an indicator of high glioblastoma risk. We also identified the cellular mechanisms of SAA1 contributing to GBM progression, which can serve as the basis for future GBM therapy.

show abstract

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

Cited by 25 publications

References 55 publications

Serum amyloid A1 isoforms display different efficacy at Toll-like receptor 2 and formyl peptide receptor 2

Serum amyloid A1 isoforms display different efficacy at Toll-like receptor 2 and formyl peptide receptor 2

Serum amyloid A1: Structure, function and gene polymorphism

Serum amyloid A1 in combination with integrin αVβ3 increases glioblastoma cells mobility and progression

Contact Info

Product

Resources

About