Xiao ng Li

A Susceptibility Locus at Chromosome 3p21 Linked to Familial Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) poses one of the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100,000. Chromosome translocation t(1;3) and frequent loss of heterogeneity on short arms of chromosome 3 and 9 have been reported to be associated with NPC, and a genome-wide scan identified an NPC susceptibility locus on chromosome 4p15.1-q12 recently. In our study, we collected samples from 18 families at high risk of NPC from the Hunan province in southern China, genotyped with a panel of polymorphic markers on short arms of chromosomes 3, 9, and 4p15.1-q12. A locus on 3p21 was identified to link to NPC with a maximum logarithm of odds for linkage score of 4.18. Fine mapping located the locus to a 13.6-cM region on 3p21.31-21.2, where a tumor suppressor gene cluster resided. Our findings identified a novel locus for NPC and provided a map location for susceptibility genes candidates. In contrast to a recent study, no significant evidence for NPC linkage to chromosomes 4 and 9 was observed.

BRD7 suppresses the growth of Nasopharyngeal Carcinoma cells (HNE1) through negatively regulating β-catenin and ERK pathways

BRD7 is a novel gene which involved NPC in our lab. Our previous studies showed that BRD7 was expressed at high level in normal nasopharyngeal epithelial tissues, but at low level in nasopharyngeal carcinoma biopsies and cell lines. In these papers, we found that ectopic expression of BRD7 can decrease cell proliferation and capability to form colonies in soft agar. FCM (Flow cytometry) assay indicated that the cell cycle progression from G1 to S phase was inhibited and the expression of cyclinD1 was significantly decreased after being transfected with BRD7 in HNE1 cells (NPC cells). To further investigate the molecular mechanism of BRD7 suppression of NPC cells growth, the cDNA microarray was performed to detect difference in gene expression profile induced by BRD7. The results indicated that 21 genes expression were changed after being transfected with BRD7 and the differentially expressed gene including α-catenin, cyclinD1, E2F3 was confirmed by western-blot. Next, we found that even though no obvious changes of the total expression of β-catenin were observed, the accumulation of β-catenin in nucleus was blocked. In addition, it was found that the expression of β-catenin was up-regulated in the complex composed of β-catenin and α-catenin in HNE1 cells induction of BRD7. So, we concluded that over-expression of BRD7 increased the expression of α-catenin which “hold” β-catenin in the complex and inhibited its accumulating in nucleus. At last, we demonstrated the c-jun, p-MEK, and p-ERK1/2 expression were down-regulated, and the Ap-1 promoter activity was inactive after being transfected with BRD7. We also found that over-expression of BRD7 can inactivate the c-jun and p-ERK1/2 after being treated with EGF in HNE1 cells. These results indicated that BRD7 played a negative role in ERK1/2 pathway. Taken together, our present results provide new insights for BRD7 function to inhibit NPC cells growth through negative regulating β-catenin and ERK1/2 pathways.

Genetic variations of EBV-LMP1 from nasopharyngeal carcinoma biopsies: potential loss of T cell epitopes

To find Epstein-Barr virus (EBV) strains with genetic variations of EBV latent membrane protein 1 (EBV-LMP1) from nasopharyngeal carcinoma (NPC), the full-length DNA of LMP1 genes from 21 NPC biopsies obtained in Hunan province in southern China was amplified and sequenced. Our sequences were compared to those previously reported by the Clustal V method. Results showed that all 21 sequences displayed two amino acid changes most frequently in LMP1 of CD4+ T cell epitopes at codons 144 (F-->I, 21/21) and 212 (G-->S, 19/21) or (G-->N, 2/21). We also show that type A EBV strain is prevalent in the cases of NPC from Hunan province with a 30-bp 18/21 deletion, and we highlight that this deletion resulted in loss of one of the CD4+ T cell-restricted epitopes. The other 3 sequences without this deletion all had a change at codon 344 (G-->D). Furthermore, in the major epitope sequence of CD8+ T cells restricted by HLA-A2, all 21 sequences showed changes at codons 126 (L-->F) and 129 (M-->I). Our study discovered that one of the 21 sequence variations harbored a new change at codon 131 (W-->C), and 5/21 specimens showed another novel change at codon 115 (G-->A) in the major epitope sequence of CD8+ T cells restricted by HLA-A2. Our study suggests that these sequence variations of NPC-derived LMP1 may lead to a potential escape from host cell immune recognition, protecting latent EBV infection and causing an increase in tumorigenicity.

Identification of a New Seven-span Transmembrane Protein: NGX6a Is Downregulated in Nasopharyngeal Carcinoma and Is Associated With Tumor Metastasis

Nasopharyngeal carcinoma (NPC)-associated gene 6 (NGX6) is a novel candidate metastasis suppressor gene that can significantly decrease the growth, motility, and invasion of NPC cells. In this study, we generated a highly specific NGX6 polyclonal antibody and analyzed its distribution in the human fetus by Western blot and immunohistochemistry. The result of the Western blot showed the protein of NGX6 had two types of isoforms, isoform a (NGX6a) and isoform b (NGX6b). Isoform a is composed of 472 amino acids with a calculated molecular mass of 52 kDa, whereas isoform b is composed of 338 amino acids with a calculated molecular mass of 37 kDa. It is predicated that there is an epidermal growth factor domain in the N terminal of both a and b isoforms, and seven transmembrane domains in NGX6a, but only two transmembrane domains in NGX6b. The expression level of NGX6a was higher than that of NGX6b in human fetal tissue. Obvious high expression of NGX6a protein presents in the nervous system and epithelial tissues of the human fetus, but the NGX6b protein (37 kDa) is mainly expressed in the nervous system. We further analyzed the tissue microarray, which contained 154 NPC biopsies and 70 non-NPC biopsies, and found that NGX6a was significantly downregulated in NPC and associated with tumor metastasis.

Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array

AbstractnPurpose. To investigate the role of the NGX6 gene in carcinoma proliferation and profile the downstream genes regulated by NGX6 in a nasopharyngeal carcinoma (NPC) cell line.nMethods. We established a NPC cell line with NGX6 overexpression by gene transfection. Subsequently, a high-density cDNA array was used to identify differentially expressed genes in NGX6-overxepressed cells. Four differentially expressed genes or EST(expressed sequence tags) were examined using Northern blot. Furthermore, flow cytometry was employed to analyze the percentages of cells in the G0-G1, S, and G2-M phase of the cell cycle in a NGX6 overexpression cell line.nResults. Fifty-five genes and ESTs were differentially expressed after NGX6 transfection in a cDNA array assay. Several genes related to cell cycle and transcription regulation were identified using this technique. Flow cytometry analysis showed NGX6 overexpression can increase the length of the G1 phase of the cell cycle in NPC cells.nConclusion. We demonstrated the existence of a panel of genes that can be regulated by NGX6. Overexpression of NGX6 can influence the distribution of the cell cycle in NPC cells. Further studies are necessary to elucidate the exact function of these genes and their relationship to NGX6 expression.

Prognostic effect of high-flux hemodialysis in patients with chronic kidney disease.

We investigated the prognostic effects of high-flux hemodialysis (HFHD) and low-flux hemodialysis (LFHD) in patients with chronic kidney disease (CKD). Both an electronic and a manual search were performed based on our rigorous inclusion and exclusion criteria to retrieve high-quality, relevant clinical studies from various scientific literature databases. Comprehensive meta-analysis 2.0 (CMA 2.0) was used for the quantitative analysis. We initially retrieved 227 studies from the database search. Following a multi-step screening process, eight high-quality studies were selected for our meta-analysis. These eight studies included 4967 patients with CKD (2416 patients in the HFHD group, 2551 patients in the LFHD group). The results of our meta-analysis showed that the all-cause death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.704, 95%CI=0.533-0.929, P=0.013). Additionally, the cardiovascular death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.731, 95%CI=0.616-0.866, P<0.001). The results of this meta-analysis clearly showed that HFHD decreases all-cause death and cardiovascular death rates in patients with CKD and that HFHD can therefore be implemented as one of the first therapy choices for CKD.