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Background: The role of human papillomavirus (HPV) may be involved in the development of esophageal cancer (EC) and the polymorphic immune response gene transporter associated with antigen processing (TAP) may be involved in HPV persistence and subsequent cancer carcinogenesis. The current study aims to provide association evidence for HPV with EC, to investigate TAP1 polymorphisms in EC and assess its association with HPV statuses and EC in Kazakhs., Methods: The HPV genotypes in 361 patients with EC and 66 controls selected from Kazakh population were evaluated using PCR. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect two SNPs of TAP1 in 150 cases comprised of 75 HPV(+) and 75 HPV(-) patients and 283 pure ethnic population of Kazakh and evaluate their associations with susceptibility to EC. A case-to-case comparison based on the genotyping results was conducted to address the function of TAP1 variants in the involvement of HPV., Results: The presence of four HPV genotypes in EC tissues - including HPV 16, 18, 31, 45 - was significantly higher at 64.6 % than those in controls at 18.2 % (P < 0.001). Such presence was strongly associated with increased risk of EC (OR 8.196; 95 % CI 4.280-15.964). The infection of HPV16, and multi-infection of 16 and 18 significantly increase the risk for developing EC (OR 4.616, 95 % CI 2.099-10.151; and OR 6.029, 95 % CI 1.395-26.057 respectively). Heterozygote of TAP1 D637G had a significantly higher risk for developing EC (OR 1.626; 95 % CI 1.080-2.449). The odds ratio for HPV infection was significantly lower among carriers of TAP1 D637G polymorphism (OR 0.281; 95 % CI 0.144-0.551)., Conclusions: HPV infection exhibits a strong positive association with the risk of EC in Kazakhs. Heterozygote of TAP1 D637G decreases susceptibility to HPV infection in patients with EC but increases susceptibility to EC among the Kazakh populations.

Invasion and metastasis are the major causes of death in patients with esophageal squamous cell carcinoma (ESCC). Epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play an important role in EMT. In this study, we investigated how TGF-β1 signaling pathways contributed to EMT in three ESCC cell lines as well as 100 patients of nomadic ethnic Kazakhs residing in northwest Xinjiang Province of China. In vitro analyses included Western blotting to detect the expression of TGF-β1/Smad and EMT-associated proteins in Eca109, EC9706 and KYSE150 cell lines following stimulation with recombinant TGF-β1 and SB431542, a potent inhibitor of ALK5 that also inhibits TGF-β type II receptor. TGF-β-activated Smad2/3 signaling in EMT was significantly upregulated as indicated by mesenchymal markers of N-cadherin and Vimentin, and in the meantime, epithelial marker, E-cadherin, was markedly downregulated. In contrast, SB431542 addition downregulated the expression of N-cadherin and Vimentin, but upregulated the expression of E-cadherin. Moreover, the TGF-β1-induced EMT promoted invasion capability of Eca109 cells. Tumor cells undergoing EMT acquire fibroblastoid-like phenotype. Expressed levels of TGF-β1/Smad signaling molecules and EMT-associated proteins were examined using immunohistochemical analyses in 100 ESCC tissues of Kazakh patients and 58 matched noncancerous adjacent tissues. The results showed that ESCC tissues exhibited upregulated expression of TGF-β1/Smad. We also analyzed the relationship between the above proteins and the patients' clinicopathological characteristics. The TGF-β1/Smad signaling pathway in human Eca109 ESCC cells may carry similar features as in Kazakh ESCC patients, suggesting that TGF-β1/Smad signaling pathway may be involved in the regulation of EMT in ethnic Kazakh patients with ESCC from Xinjiang, China.

Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.

The involvement of human papillomavirus (HPV) in the carcinogenesis of esophageal squamous carcinoma remains undetermined. However, three genome-wide association studies of esophageal cancer have identified a shared susceptibility locus at 10q23 (rs2274223: A5780G) in phospholipase C epsilon 1 (PLCE1). The current study aims to present a comprehensive and novel spectrum about the HPV genotype distribution of esophageal carcinoma in Kazakhs and assess its association with PLCE1 polymorphisms. The HPV genotypes in 183 patients with esophageal cancer and 89 controls selected from the Kazakh population were evaluated using the HPV gene chip. The PLCE1 rs2274223 variant was genotyped in esophageal carcinoma patients by MALDI-ToF Mass Spectrometry. The presence of seven HPV genotypes in esophageal carcinoma tissues-including HPV 16, 18, 35, 52, 6, 11, 43-was significantly higher at 31.7% than those in controls at 9.0% (P < 0.001). Such presence was strongly associated with increased risk of esophageal carcinoma (OR 4.70; 95% CI 2.13-10.36). Among all HPV genotypes detected, HPV16 was the most common genotype identified (29.0%, OR 4.13; 95% CI 1.87-9.13), which is significantly associated with well-differentiated esophageal carcinoma (P = 0.037). HPV-positive patients were generally younger than HPV-negative patients (70.1% vs. 29.3%, P = 0.013). PLCE1 rs2274223 genotypes AG and AG/GG were significantly associated with HPV-positive patients with esophageal carcinoma (OR 2.05, 95% CI 1.03-4.08 and OR 1.98, 95% CI 1.02-3.84, respectively). These findings suggest that heterozygote of PLCE1 rs2274223 increases susceptibility to HPV infection in patients with esophageal carcinoma among the Kazakh populations., (© 2013 Wiley Periodicals, Inc.)

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with dismal prognosis and high incidence and mortality in Kazakh population. MiR-34a, a direct p53 target gene, possesses tumor-suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. The reduced expression of miR-34a by methylation in various cancers has been reported., Methods: To determine whether aberrant miR-34a methylation occurs in esophageal cancer, the DNA methylation of 23 CpGs sites in the miR-34a promoter was quantitatively analyzed in relation to the translation initiation site by MALDI -TOF mass spectrometry in 59 ESCC tissues and 34 normal tissues from the Kazakh population. Real-time PCR was used to detect the inhibition of miR-34a expression levels and to evaluate their association with methylation., Results: We found that miR-34a is more frequently methylated in ESCC (0.133 ± 0.040) than in controls (0.066 ± 0.045, P < 0.01). A nearly two-fold increase in miR-34a expression for the hypomethylated promoter was found in normal esophageal tissues than ESCC with hypermethylation (P <0.0001), pointing to a negative relationship between miR-34a CpG sites methylation and expression(r = -0.594, P = 0.042). The hypermethylation of miR-34a CpG&#95;8.9 was associated with the advanced UICC stage III/IV of the esophageal cancers, and the hypermethylation of CpG&#95;8.9 and CpG&#95;5 of miR-34a was significantly correlated with lymph node metastasis., Conclusions: Our findings suggest that miR-34a is involved in the etiology of ESCC and that hypermethylated miR-34a is a potential biomarker for ESCC diagnosis and prognosis. Moreover, targeting miR-34a methylation by demethylating agents may offer a novel strategy for anticancer therapy of ESCC.

Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15-6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh ESCC in XinJiang, China.