Xiaomei Lu

Northwestern China: a place to learn more on oesophageal cancer. Part one: behavioural and environmental risk factors.

Oesophageal squamous cell carcinoma (OSCC) remains a public health problem in many countries, especially in emerging and developing countries. Epidemiology of OSCC is characterized by marked differences in prevalence between countries/regions/ethnical groups. The highest incidence in the world is reached by populations living in specific areas of northwestern Xinjiang, China where age-adjusted mortality may reach 150 of 100 000. In fact, there are also marked differences among the various geographical areas and the various ethnic groups within the region, which suggests specific risk factors. Behavioural factors include those factors which are common to all ‘high-risk populations’, such as tobacco smoking and alcohol drinking. However, the very unusual sex ratio (1.2 : 1.0) and young age range of OSCC occurrence suggests the involvement of additional early risk factors shared by males and females, and which are different from those studied in other ‘high-risk’ areas of the world, including China, such as LinXian area. These include drinking very hot and salted tea, boiled with milk; a diet rich in meat, especially salted, dry and/or smoked meat, and dairy products; and a diet poor in fresh fruit and vegetables. The combination of hot drinks (such as milk, tea and soups) and high-degree spirit drinks, and hard food (bread, meat and cheese), together with poor oral hygiene and tooth loss, is likely to add mechanical injury of the oesophagus to other factors linked to climate characteristics of the area (drought) and dietary habits, which promote a sodium and nitrosamine-rich diet. Association of early and severe hypertension in the same populations at high risk of OSCC might likely raise more attention. Human papilloma virus (HPV) infection, and especially HPV 16/18 E6/E7, with gene mutations and association with p53 overexpression, may contribute to the extremely high incidence of OSCC observed in Xinjiang, and could be accessible to prevention. Infection may especially be a crucial additional factor in the Uygur population in which not only HPV infection but also infection with other oncogenic viruses, such as HHV8, are highly prevalent. Genetic polymorphism might interact with viruses and/or viral products to promote carcinogenesis. These observations in northwestern China suggest that usually neglected factors, such as sodium excess and viral infection, could be taken into more account when studying OSCC risk factors in other parts of the world, especially Europe.

Human herpesvirus-8 in northwestern China: Epidemiology and characterization among blood donors

BackgroundHuman herpes virus 8 (HHV-8) is the etiologic agent associated with development of classical, AIDS-related, iatrogenic, and endemic Kaposis sarcoma (KS). Several studies provide strong evidence that HHV-8 can be transmitted by blood transfusion. We evaluated the seroprevalence and potential risk factors of HHV-8 infection in blood donors in one region. We surveyed HHV-8 infection among 4461 blood donors in Xinjiang, China, a unique endemic area for HHV-8 and KS.ResultsThe HHV-8 seroprevalence was higher in local minority groups which comprise most KS cases in China, than in Han people. HHV-8 prevalence was 18.6% in the Han ethnic group, 25.9% in Uygur subjects, 29.2% in Kazak subjects, 36.8% in Mongolian subjects, and 21.9% in other ethnic groups. In several subgroups, the time of donation of whole blood seemed to be a risk factor. In HHV-8-seropositive subjects, a larger fraction of local minorities (23.9%) had high HHV-8 titers than that of Han subjects (9.2%). HHV-8 infection was associated with ethnicity and residence.ConclusionHHV-8 seroprevalence was significantly high among blood donors in Xinjiang, where the prevalence of KS correlates with HHV-8 prevalence and titers in Uygur and Kazak ethnic groups. Blood exposure represented by the frequency of blood donation indicated a possible blood-borne transmission route of HHV-8 in Xinjiang. Detecting anti-HHV-8 antibodies before donation in this region is therefore important.

Northwestern China: a place to learn more on oesophageal cancer. Part two: gene alterations and polymorphisms.

In the first part of this review, some behavioural and environmental risk factors playing important roles in the development of Kazakh’s oesophageal squamous cell carcinoma (OSCC) were presented. Although all individuals have been exposed to the same environment and share the same behaviour, some of them will not develop OSCC. Thus, gene susceptibility and/or gene polymorphism are unavoidably involved. The molecular events underlying the initiation and progression of OSCC remain, however, poorly understood. In the second part of our review of OSCC in northwestern China, especially in the high-risk Kazakh population, some recent progress in the study of the molecular biology underlying oesophageal carcinogenesis, including chromosome deletions and loss of heterozygocity, polymorphisms of genes involved in xenobiotic metabolizing and DNA repair, and genetic alterations of transcriptional factors and apoptosis genes are presented. Results obtained in this high-risk population are compared with those obtained in other areas that are also known to be at high risk for OSCC, and whenever possible, with those studies performed in European, American or Australian low-risk areas. Recent advances in the investigation of the proteomics and microRNA biomarkers potentially useful for an earlier diagnosis and/or prognosis of OSCC are also discussed.

Lack of association of functional variants in alpha-ENaC gene and essential hypertension in two ethnic groups in China.

Background: It has been proposed that subtle genetic changes in epithelial sodium channel (ENaC) subunits might be at the origin of less rare forms of hypertension. In some populations, subtle functional genetic changes in ENaC genes associated with essential hypertension were indeed observed. To further test this hypothesis, we observed the role of three functional variants G2139A, A334T and A663T in the alpha-ENaC gene on essential hypertension in two Chinese minority groups, the Kazaks and Uyghurs. Methods: A population-based case-control study was carried out in the two populations mentioned above. Results: The distribution of genotype and allele frequencies of G2139A, A334T and A663T did not differ significantly between hypertensive subjects and control subjects in both Kazak and Uyghur populations. No significant associations of the three polymorphisms with hypertension were observed in both populations in univariate and multivariate logistic regression analysis by applying dominant, additive and recessive models. Haplotype-based association analysis based on G2139A, A334T and A663T did not show significant association between hypertensive subjects and control subjects in both populations. Conclusions: For the above variants, we did not confirm the hypothesis that subtle genetic changes in alpha-ENaC subunits might be at the origin of essential hypertension in our populations.

MicroRNA-21 Promotes Cell Growth and Migration by Targeting Programmed Cell Death 4 Gene in Kazakh’s Esophageal Squamous Cell Carcinoma

Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth most common cause of cancer death. There are two main types of EC—squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Although some advances in the exploration of its possible etiological mechanism were made recently including behaviors and environmental risk factors as well as gene alterations, the molecular mechanism underlying ESCC carcinogenesis and progression remains poorly understood. It has been reported that miR-21 was upregulated in most malignant cancers, the proposed mechanism of which was through suppressing expression of programmed cell death 4 (PDCD4). In present study, it is firstly reported that miR-21 was upregulated in Kazakhs ESCC and that miR-21 played a negative role in regulating PDCD4 using in situ hybridization (ISH) and luciferase reporter approach. Morever, in model of ESCC xenografted nude mice, miR-21 maybe used as an effective target in the treatment. The present results demonstrated that miR-21 may be a potential therapeutic target in management of ESCC.

Polymorphisms of COMT and XPD and risk of esophageal squamous cell carcinoma in a population of Yili Prefecture, in Xinjiang, China

Objective: To investigate polymorphisms of COMT (Rs4680) and XPD (Rs13181) and risk of esophageal squamous cell carcinoma (ESCC) in a population from Yili Prefecture, Xinjiang, China. Methods: A hospital-based case–control study was designed. Genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Odds ratios (OR) and 95% confidence intervals (CI) were analysed using unconditional logistic regression. Results: An increased risk of ESCC was discovered with COMT in relation to the frequency of the presence of the A allele (Rs4680; OR 1.30, 95% CI 1.00–1.68). An individual with combined COMT 158 (Val/Met or Met/Met) and XPD 751 (Lys/Gln or Gln/Gln) genotype had an increased ESCC risk. Conclusions: Polymorphic variation in COMT Val158Met and XPD Lys751Gln may be important for ESCC susceptibility.

Under-expression of annexin A2 is associated with Kazakh's esophageal squamous cell carcinoma.

The aim of the study was to identify candidate biomarkers for esophageal squamous cell carcinoma (ESCC) in Kazakh ethnic in Xinjiang as well as to reveal the potential role of Annexin A2 in ESCC carcinogenesis and progression. Five paired of Kazakhs ESCC tissues (T) and matched adjacent morphologically normal tissues (N) were separated by two‐dimensional electrophoresis (2‐DE) and differential proteins were identified by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF–MS). Annexin A2 was identified as a down‐regulated protein in Kazakhs ESCC and further validated by immunohistochemistry (IHC) in 77 Kazakhs ESCC formalin‐fixed paraffin‐embeded (FFPE) samples. The expression level of Annexin A2 protein significantly correlated with the degree of ESCC differentiation and depth of invasion. For clarification of the role of Annexin A2 in regulating cell phenotype, in vitro eukaryotic expression vectors harboring full length Annexin A2 (pCMV‐XL5‐Annexin A2) was tranfected into Eca109 cells, and transfection effects were evaluated by RT‐PCR and Western blotting analysis, respectively. Functionally, there was a significant decrease in cell proliferation, migration, and invasion capability in Eca109 with transfected pCMV‐XL5‐Annexin A2 compared to the controls. Furthermore, up‐regulating Annexin A2 can significantly cause cell cycle arrest at the G2 phase, but no apoptosis was induced. Together, our findings suggested that Annexin A2 was involved in malignant phenotype and was a potential biomark for molecular classification in ESCC.

IL-1β from M2 macrophages promotes migration and invasion of ESCC cells enhancing epithelial-mesenchymal transition and activating NF-κB signaling pathway

Despite the phenotype has been established that M2 macrophages promotes the metastasis of ESCC, question still remains as to how the M2 macrophages facilitated metastasis of ESCC cells. To begin with, immunohistochemistry was performed to detect the expression of CD163, one typical surface marker of M2 macrophages in 90 paired ESCC and its normal controls after meta‐analyzing the relevant studies regarding M2 macrophages in ESCC, confirming that infiltration of M2 macrophages was significantly linked with lymph node metastasis, T classification, and inferior overall survival of ESCC. To explore the mechanism behind, protein factors secreted by M2 macrophages were identified using antibody microarray. Six different significantly differential protein factors were screened out, including IL‐1β, TIMP1, IL‐1α, MDC, TGF‐β1, and TGF‐β2. Among which, IL‐1β was picked up as cytokine as interest based on previous reports and its absolute fold. Functional analysis of IL‐1β showed that IL‐1β was able to promote migration and invasion of ESCC cells, enhancing epithelial‐mesenchymal transition, and activating NF‐κB pathway. Our study supports the promoting role of M2 macrophages in metastasis of ESCC cells, enriching the profile of protein factors released from M2 macrophages.

MCP2 activates NF-κB signaling pathway promoting the migration and invasion of ESCC cells: MCP2 activates NF-κB promoting motility

MCP2, aliased CCL8, has been suggested to be implicated in the metastasis of cancer cells; however, no direct evidence has been established in esophageal squamous cell carcinoma (ESCC). In our present study, to investigate the role MCP2 played in the metastasis of ESCC cells; in vitro cell co‐culture system was established. Wound‐healing and Transwell assays were used to evaluate the migratory and invasive variation of ESCC cells before and after treatment with recombinant human MCP2. It was shown that MCP2 was able to activate the NF‐κB signaling pathway inducing the epithelial‐mesenchymal transition (EMT) and promoting the migration and invasion of ESCC cells in vitro. Our study provides an alternative working mechanism for M2 macrophage mediated the metastasis in tumor microenvironment in ESCC.