Treadmill training improves cognitive function by increasing IGF2 targeted downregulation of miRNA-483.

Optimal exercise can promote the development of cognitive functions. Nevertheless, mechanisms that elicit these positive effects of exercise still need to be elucidated. Insulin-like growth factor 2 (IGF2) is known to act as a potent enhancer of memory and cognitive functions, whereas the mechanism by which IGF2 regulates cognitive functions in terms of moderate treadmill exercise remains largely vague. In the study, rats were subjected to low-, moderate-, and high-intensity treadmill training for 6 weeks. Then, the Morris water maze test was used to investigate spatial learning and memory ability in rats subjected to treadmill exercises of different intensities. Subsequently, gene chip and bioinformatics analyses were used to explore IGF2 and predict target microRNAs (miRNAs). Quantitative real-time polymerase chain reaction, western blot, and immunofluorescence analysis were performed to detect the levels of IGF2. Furthermore, IGF2-small interfering RNA, the miRNA-483-mimic, and the miRNA-483-inhibitor were transfected to determine the role of IGF2 and miRNA-483 in the growth of hippocampal neurons. The results of the Morris water maze test showed that moderate-intensity treadmill training enhanced cognitive functions; meanwhile, the expression of IGF2 was significantly upregulated in the hippocampus after moderate-intensity treadmill exercise. From databases, miRNA-483 was screened and predicted as the target gene of IGF2. Moreover, silencing IGF2 inhibited neurite growth in the hippocampus of rats, the miRNA-483-inhibitor ameliorated silencing IGF2 induced impairment of hippocampal neurons. These findings suggested that treadmill training could enhance cognitive functions, wherein the underlying mechanism involved an increase in the expression of IGF2 and downregulation of miRNA-483.

Characteristics of olfactory ensheathing cells and microarray analysis in Tupaia belangeri (Wagner, 1841).

Tree shrews are most closely related to the primates and so possess a number of advantages in experimental studies; they have been used as an animal model in bacterial and virus infection, cancer, endocrine system disease, and certain nervous system diseases. Their olfactory ensheathing cells (OECs) are able to release several cytokines to promote neuronal survival, regeneration and remyelination. The present study used western blot analysis to identify antibody specificity in protein extracts from whole tree shrew brains to identify the specificity of p75 nerve growth factor receptor (NGFR) derived from rabbits (75 kDa). OECs were cultured and isolated, then stained and identified using the antibodies for p75NGFR. To investigate the capacity of OECs to express cytokines and growth factors, microarray technology was used, and the analysis revealed that OECs were able to express 9,821 genes. Of these genes, 44 genes were from the neurotrophic factor family, which may indicate their potential in transplantation in vivo. The present study considered the function of OECs as revealed by other studies, and may contribute to future research.

Bone Marrow Mesenchymal Stem-Cell Transplantation Promotes Functional Improvement Associated with CNTF-STAT3 Activation after Hemi-Sectioned Spinal Cord Injury in Tree Shrews.

Hemi-sectioned spinal cord injury (hSCI) can lead to spastic paralysis on the injured side, as well as flaccid paralysis on the contralateral side, which can negatively affect a patient's daily life. Stem-cell therapy may offer an effective treatment option for individuals with hSCI. To examine the role of bone marrow mesenchymal stem cells (BMSCs) transplantation on hSCI and explore related mechanisms in the tree shrews, here, we created a model of hSCI by inducing injury at the tenth thoracic vertebra (T10). Hoechst 33342-labeled BMSCs derived from adult tree shrews were isolated, cultured, and implanted into the spinal cord around the injury site at 9 days after injury. The isolated BMSCs were able to survive, proliferate and release a variety of neurotrophic factors (NTFs) both in vitro and in vivo. At 28 days after injury, compared with the sham group, the hSCI group displayed scar formation and dramatic elevations in the mean interleukin 1 beta (IL-1ß) density and cell apoptosis level, whereas the expression of signal transducer and activator of transcription 3 (STAT3) and ciliary neurotrophic factor (CNTF) mRNA was reduced. Following BMSC transplantation, motoneurons extent of shrinkage were reduced and the animals' Basso, Beattie, and Bresnahan (BBB) locomotion scale scores were significantly higher at 21 and 28 days after injury when compared with the injured group. Moreover, the hSCI-induced elevations in scar formation, IL-1ß, and cell apoptosis were reduced by BMSC transplantation to levels that were close to those of the sham group. Corresponding elevations in the expression of STAT3 and CNTF mRNA were observed in the hSCI + BMSCs group, and the levels were not significantly different from those observed in the sham group. Together, our results support that grafted BMSCs can significantly improve locomotor function in tree shrews subjected to hSCI and that this improvement is associated with the upregulation of CNTF and STAT3 signaling.

Plasma microRNA-16-5p, -17-5p and -20a-5p: Novel diagnostic biomarkers for gestational diabetes mellitus.

AIM: To explore whether plasma microRNA-16-5p, -17-5p and -20a-5p can be used as diagnostic biomarkers in gestational diabetes mellitus (GDM) and to investigate the relationship between those microRNAs and the risk factors of GDM (body mass index [BMI], insulin resistance [IR] and tumor necrosis factor-α (TNF-α)). METHODS: A total of 85 pregnant women with GDM and 72 pregnant women without GDM were enrolled in this study. The plasma concentration of microRNAs (microRNA-16-5p, -17-5p, -19a-3p, -19b-3p, -20a-5p) was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spearman's correlation analysis was used to evaluate the correlation between those microRNAs and the risk factors of GDM, and receiver operating characteristic curve analysis was used to evaluate diagnostic sensitivity and specificity. RESULTS: Compared with non-GDM women, the relative and absolute expression of plasma microRNA-16-5p, -17-5p, -20a-5p from GDM women were significantly upregulated, when those women were diagnosed as GDM. During pregnancy, the expression of those microRNAs from GDM women also were significantly upregulated. The expression of those microRNAs was also positively correlated with IR, a risk factor of GDM. Plasma microRNA-16-5p, -17-5p, -20a-5p reflected an obvious separation between GDM women and non-GDM women, with areas under the curve of 0.92 (95%CI: 0.871-0.984), 0.88 (95%CI: 0.798-0.962), and 0.74 (95%CI: 0.618-0.870), respectively, cut-offs >2554, 1820, 3886 copies/µL, respectively; sensitivity 41.6%, 21.4% and 17.8%, respectively; and specificity 95.8%, 95.4% and 95.4%, respectively. CONCLUSION: Plasma microRNA-16-5p, -17-5p and -20a-5p are potential diagnostic biomarkers in GDM.

Neuroprotective effect of breviscapine on traumatic brain injury in rats associated with the inhibition of GSK3ß signaling pathway.

Breviscapine, a standardized Chinese herbal medicine extracted from Erigeron breviscapine, has been widely used to treat cerebrovascular diseases. However, there are no reports about the neuroprotective effects and underlying molecular mechanisms of breviscapine on traumatic brain injury (TBI). Therefore, this study was aimed to investigate the effects of breviscapine on rats with TBI insult and illuminate the underlying mechanism. We created a traumatic brain-injured model with breviscapine lateral ventricle injection and evaluated the expressional changes of glycogen synthase kinase 3 beta (GSK3ß) as well as the GSK3ß-involved signaling pathways including apoptosis and axonal growth. At 7, 14, 21days after injection, we found a great reduction of motor disability in TBI rats following breviscapine treatment, which was accompanied with a notably increased expression of phospho-Ser9-GSK3ß (p-Ser9-GSK3ß) and decreased expression of phosphor-Try216-GSK3ß (p-Try216-GSK3ß) at 7days after injection. Concomitantly, an enhanced expression of synaptic marker synaptophysin (SYP) together with a weakened expression of pro-apoptotic caspase3 was observed after TBI rats were treated with breviscapine. Terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) immunohistochemical assay and SYP immunofluorescence staining also confirmed the result. This study suggests that breviscapine inhibits the GSK3ß signaling pathway to promote neurobehavioral function following neurotrauma. These events may provide a new insight into the mechanism of breviscapine treating brain injury.

Releasing of Herpes Simplex Virus Carrying NGF in Subarachnoid Space Promotes the Functional Repair in Spinal Cord Injured Rats.

BACKGROUND: Spinal cord injury (SCI) is a serious disease which can lead to bad consequence in patients. Gene therapies, as an effective strategy, have been developed for the treatment of several diseases. But the effect for the treatment of SCI is also waiting to be practiced. OBJECTIVE: Here, we explored the effect of NGF administration carried by herpes simplex virus (HSV) in the injured spinal cord. METHODS: Transgenic recombinant containing human NGF was constructed by using pSP72 plasmid, then enveloped by non-replication HSV vector with deleted ICP27, ICP4 and ICP34.5 genes. Next, HSV recombinant carrying NGF was injected into cerebrospinal fluid in the lumbar cord to detect the effect of NGF for the improvement of motor function, indicated by BBB score. Meanwhile, IHC, QPCR and WB were used to confirm the NGF transduction. RESULTS: After SCT, BBB score was largely decreased, followed by a gradual limit recovery with time going on. Q-PCR confirmed that the mRNA expression of NGF was increased in the spinal cord at 28 days post-operation, compared with that in the sham group, which suggests endogenous NGF may be available to the limit repair of motor function. Moreover, HSV carried NGF was injected into subarachnoid space of the spinal cord, which results in a significant functional improvement in hindlimbs from 7dpo to 49dpo. The level of NGF in HSV-NGF administrated group was obviously higher than that in the empty vector group and SCT group, only. CONCLUSION: Our results demonstrate that releasing of HSV-NGF-recombinant in subarachnoid space, can effectively improve the motor function in hindlimbs of rats subjected to SCT, which supports that strategy of HSV carrying NGF may be used for the treatment of SCI in future clinic practice.

ABCA1 expression in macrophages of allogeneic hematopoietic stem cell transplantation patients with severe infection undergoing continuous blood purification.

BACKGROUND: Excessive activation of the inflammatory mediator cascade after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients is associated with high mortality. Many studies have shown that continuous blood purification (CBP) could improve the prognosis of allo-HSCT patients with severe infection. However, the exact mechanism remains unclear. The aim of this study was to observe the effect of CBP on the expression of ATP-binding cassette transporter A1 (ABCA1) in macrophages, and to investigate the interventional effects of CBP on serum cytokine in allo-HSCT patients with severe infection. METHODS: A total of 26 allo-HSCT patients with severe infection were included in this study. Before CBP and after CBP, blood samples were collected to observe hepatic and renal function, and the serum levels of TNF-α, IL-1, IL-6, and IL-10 were detected via ELISA. The THP-1 macrophages were exposed to serum samples obtained from patients at specific time points during CBP to test the changes of ABCA1 in macrophages by real-timePCR and Western blotting. RESULTS: Serum creatinine, alanine aminotransferase, and C reaction protein (CRP) levels decreased significantly after CBP. Moreover, TNF-α, IL-1, and IL-6 serum levels decreased significantly, but IL-10 level increased significantly after CBP (P<.05). After CBP, ABCA1 expression levels were higher than those before CBP, and ABCA1 expression was significantly increased with the supplementation of CBP (P<.05). CONCLUSIONS: CBP improved the condition of allo-HSCT patients with severe infection. CBP may be a potent up-regulator of the ABCA1 levels in macrophages of allo-HSCT patients with severe infection.

Identification of phosphorylated MYL12B as a potential plasma biomarker for septic acute kidney injury using a quantitative proteomic approach.

Acute kidney injury (AKI) is a common and increasingly encountered complication in hospitalized patients with critical illness in intensive care units (ICU). According to the etiology, Sepsis-induced AKI (SAKI) is a leading contributor to AKI and significantly has very poor prognosis, which might be related to the late detection when the elevation of BUN and serum creatinine (SCr) is used. Many genes are up-regulated in the damaged kidney with the corresponding protein products appearing in plasma and urine. Some of these are candidate biomarkers for more timely diagnosis of SAKI. Therefore, extensive research efforts over this past decade have been directed at the discovery and validation of novel SAKI biomarkers to detect injury prior to changes in kidney function, a number of serum and urinary proteins, including NGAL, KIM-1, cystatin-C, IL-18, and L-FABP, have been identified for predicting SAKI before a rise in BUN and serum creatinine in several experimental and clinical trainings. Unfortunately, an ideal biomarker of SAKI with highly sensitivity and specificity has not been identified yet. Recent progresses in quantitative proteomics have offered opportunities to discover biomarkers for SAKI. In the present study, kidney tissue samples from SAKI mice were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE), and 4 up-regulated proteins, which were actin (ACTB), myosin regulatory light chain 12B (MYL12B), myosin regulatory light polypeptide 9 (MYL9), and myosin regulatory light chain 12A (MYL12A) were identified by matrix assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Among all the varied proteins, MYL12B was validated by western blot. Interestingly, there was no change between the SAKI and control kidney tissues, however, phosphorylated MYL12B was detected to be consistent with the proteomics data. Furthermore, phosphorylated MYL12B was found similarly to be increased in SAKI plasma, while MYL12B was changeless in plasma of control group. Taking together, phosphorylated MYL12B may be employed as a potential plasma biomarker for the early diagnosis of SAKI.

An investigation on the polymorphisms of two DNA repair genes and susceptibility to ESCC and GCA of high-incidence region in northern China.

AIM: To investigate the possible association of three SNPs, XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a population of northern China. METHODS: XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G SNP were genotyped by polymerase-chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis in 583 cancer patients (329 ESCC and 254 GCA) and 614 healthy controls. RESULTS: The genotype distribution of the XRCC2 C41657T in ESCC and GCA patients were significantly different from that in healthy controls (P values = 0.04 and 0.04 respectively). And a significant difference was found in the allele distribution of GCA patients from that in controls (P = 0.01). The XRCC2 C41657T polymorphism was associated with a modest enhancement in ESCC risk and GCA risk: OR for C/T genotype was 1.38 (1.01-1.89) in GCA risk and for T/T genotype was 2.24 (1.10-4.57) in ESCC risk. When stratified for age, smoking status and family history of UGIC, the C/T genotype showed a modest significant trend on the risk of GCA patients in the groups of age < or =50 years and non-smokers, the adjusted OR were 2.84 (1.21-6.66) and 1.62 (1.06-2.49). The T/T genotype significantly increased the susceptibility of GCA patients in negative family history of UGIC (3.04, 1.02-8.32) and to ESCC patients in the group of age >50 years (3.03, 1.31-6.98), Negative family of UGIC (3.03, 1.12-7.07) and smokers (2.64, 1.02-6.83). The genotype and allele distribution of XRCC2 G4234C and XRCC3 A17893G in ESCC and GCA patients were not significantly different from that in healthy controls (all P values were above 0.05). CONCLUSION: In this study, we found that the C41657T polymorphism of XRCC2 genes might modify the risk of ESCC and GCA development.

Polymorphisms of the DNA repair gene xeroderma pigmentosum groups A and C and risk of esophageal squamous cell carcinoma in a population of high incidence region of North China.

AIM: Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity (DRC) and genetic susceptibility to different cancers. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of xeroderma pigmentosum group A (XPA) and XPC can influence the risk of esophageal squamous cell carcinoma (ESCC). METHODS: In this report, one SNP of XPA and three SNPs of XPC were genotyped by polymerase-chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) assay in 327 ESCC patients and 612 healthy controls in a high incidence region of North China. RESULTS: Family history of upper gastrointestinal cancers (UGIC) may increase the risk of developing ESCC. The overall genotype and allelotype distributions of XPA A23G in ESCC patients were significantly different from that in healthy controls (P < 0.05). The A/G + G/G genotype significantly decreased the risk of developing ESCC compared with A/A genotype. When stratified for family history of UGIC, compared with A/A genotype, A/G + G/G genotype significantly decreased the risk of ESCC in groups with negative history of UGIC. The overall genotype and allelotype distributions of XPC intron 9 PAT(+/-) and exon 15 Lys939Gln and exon 8 Val499Ala in ESCC patients were not significantly different from that in healthy controls (P > 0.05). When stratified for smoking status and UGIC family history, compared with A/A genotype, C/C genotype of exon 15 Lys939Gln significantly increased the risk of developing ESCC in non-smoker group. CONCLUSIONS: We concluded that XPA23 polymorphism may be useful markers for identifying individuals at risk of developing ESCC. C/C genotype of XPC exon 15 may be one of the factors that affect the risk of developing ESCC in nonsmoking population in the high incidence region of China.

[The association of XRCC2 gene polymorphism with susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in China].

OBJECTIVE: To investigate the possible association of single nucleotide polymorphism (SNP) at the 41657C/T position and 4234G/C position of X-ray repair cross-complementing gene 2 (XRCC2) with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region, Ci county and She county of Hebei. METHODS: The genotypes of XRCC2 41657C/T and 4234G/C SNPs were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis in 330 ESCC patients, 254 GCA patients and 629 healthy controls. RESULTS: The genotype frequency of XRCC2 41657C/T in ESCC patients (67.8%, 26.4% and 5.8%) was significantly different from that in controls (68.8%, 28.8% and 2.4%; chi square was 7.43, P was 0.02). Compared with CC genotype, TT genotype significantly increased the risk of developing ESCC (OR=2.12, 95%CI: 1.03-4.35). The genotype (59.9%, 35.8% and 4.3%) and allelotype distributions ofXRCC2 41657C/T in GCA patients were significantly different from that in controls (chi square was 7.46 and 7.23, P was 0.02 and 0.01). Compared with CC genotype, CT genotype significantly increased the risk of developing GCA (OR=1.38, 95%CI: 1.01-1.89). The genotype and allelotype distributions of the 4234G/C SNPs in ESCC and GCA patients were not significantly different from that in controls (all P values were above 0.05). Compared with GG genotype, the CG and CC genotype of XRCC2 4234G/C did not show significant effect on the risk of developing ESCC and GCA. When the two XRCC2 SNPs were combined analyzed, the haplotype distribution in GCA patients was significantly different from that in controls (chi square was 13.28, P was less than 0.01). Compared with 41657C/4234G haplotype, 41657C/4234C and 41657T/4234G haplotypes significantly increased the risk of developing GCA (OR were 1.44 and 1.55, 95%CI were 1.06-1.95 and 1.18-2.02, respectively). CONCLUSION: In high incidence region of Hebei province, we conclude that XRCC2 41657C/T polymorphism has a potential to be a susceptibility factor for ESCC and GCA while XRCC2 4234G/C polymorphism may not provide a useful marker to predict susceptibility to ESCC and GCA. However, the 41657C/4234C and 41657T/4234G haplotypes might increase the risk of developing GCA.

[Study on the association between STK15 Phe31Ile polymorphisms and esophageal squamous cell carcinoma].

OBJECTIVE: To study the relation between single nucleotide polymorphism(SNP) at the 91T-->A(Phe31Ile) position of the STK15 gene and the susceptibility of esophageal squamous cell carcinoma (ESCC) in She county--a ESCC high incidence region in North China. METHODS: Polymerase-chain reaction(PCR)-restriction fragment length polymorphism (RFLP) analysis was used to detect the genotypes of STKl5 Phe31Ile(91T-->A) SNP, and the samples came from 296 ESCC patients and 302 healthy controls. RESULTS: The risk of ESCC significantly increased in the group which had been smoking or having a family history of upper gastrointestinal cancer (UGIC) (the OR = 1.68 and 1.77, 95% CI: 1.34-2.10 and 1.44-2.19, respectively). Rates of the three genotypes (Phe/Phe, Phe/Ile, Ile/Ile) of the STK15 Phe31Ile (91T-->A) SNPs in ESCC patients were 11.5%, 34.8% and 53.7%, respectively, and were not significantly different from that in the healthy group (11.9%, 36.8% and 51.3%) (chi2 = 0.35, P = 0.84). When compared to Phe/Phe genotype, Phe/Ile and Ile/Ile of STK15 91T-->A(Phe31Ile)did not show effect on the risk of ESCC according to the odds ratio results which were 0.98 (95% CI: 0.57-1.69) and 1.09 (0.65-1.82) respectively. STK15 91T-->A (Phe31Ile) SNP also did not significantly influence on the development of ESCC even the samples were stratified by sex, smoking status and family history of upper gastrointestinal cancer. CONCLUSION: The STK15 Phe31Ile(91T-->A) polymorphisms seemed irrelevant with the risk of ESCC in She county.

[Correlations of XRCC5 polymorphisms to genetic susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in a high incidence region].

BACKGROUND & OBJECTIVE: XRCC5 is a repair gene for DNA double-strand break. Its abnormal expression and dysfunction is correlated to tumorigenesis and development. This study was to investigate the correlations of XRCC5 polymorphisms to genetic susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region, Cixian and Shexian counties of Hebei Province, China. METHODS: The genotypes of XRCC5 single nucleotide polymorphisms (SNPs), C74468A and G74582A, in 329 ESCC patients, 255 GCA patients, and 631 healthy controls were detected by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis. RESULTS: The overall genotype and allelotype distributions of XRCC5 C74468A and G74582A in ESCC and GCA patients were not significantly different from those in healthy controls (P>0.05). When stratified by smoking status and family history of upper gastrointestinal cancer (UGIC), A allele (A/C+A/A genotype) of C74468A significantly reduced the risk of developing ESCC and GCA in positive UGIC family history group [age, sex, and smoking status adjusted odds ratios (ORs) were 0.58 and 0.61, 95% confidence intervals (CIs) were 0.38-0.90 and 0.38-0.97, respectively]û G allele (A/G+G/G genotype) of G74582A significantly reduced the risk of developing GCA in positive UGIC family history group (age, sex, and smoking status adjusted OR=0.63, 95% CI=0.40-0.98). Combined analysis of the 2 XRCC5 SNPs showed that the haplotype distribution in ESCC and GCA patients was also not significantly different from that in healthy controls (P> 0.05). CONCLUSIONS: In the population with positive UGIC family history in the high incidence region of Hebei Province, individuals with A allele of XRCC5 C74468A might have low risk of developing ESCC and GCA, however, individuals with G allele of XRCC5 G74582A might only have low risk of developing GCA.

[The association of MMP-13 polymorphism with susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma].

Matrix metalloproteinase-13 (MMP-13) belongs to a family of enzymes that degrade all components of the extracellular matrix. Polymorphism in the promoter region of the MMP-13 gene may modify its transcriptional activity and protein level. This study was designed to investigate the correlation of MMP-13 A-77G single nucleotide polymorphism (SNP) with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac carcinoma (GCA) in a population from a high-incidence region of Hebei province. MMP-13 promoter SNP (A-77G) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 316 ESCC patients, 243 GCA patients and 609 healthy controls. The overall genotype and allelotype distributions of MMP-13 in ESCC and GCA patients were not significantly different from those in healthy controls (P>0.05). When stratified for smoking status, the A/A, A/G, G/G genotype frequencies of MMP-13 in GCA patients and smoker controls group were 27.1%, 44.1%, 28.8% and 17.8%, 60.5%, 21.7% respectively. There was a significant difference between the two groups (chi2=9.01, P=0.01). The A/G genotype frequency in GCA patients was significantly lower than that in the controls, when compared to the A/A genotype, suggesting that individuals with the A/G genotype may have reduced susceptibility to GCA in the smoker group (OR=0.48, 95% CI=0.280.83). However, the G/G genotype showed no significant influence on the risk of developing GCA. Thus, in the region of Hebei Province where there is a high incidence of GCA and ESCC, the MMP-13 A-77G SNP may not be associated with cancer susceptibility. The A/G genotype may confer protection against GCA for smokers.

[Correlation of XPC Ala499Val and Lys939Gln polymorphisms to risks of esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma].

BACKGROUND & OBJECTIVE: Xeroderma pigmentosum group C(XPC) gene is involved in nucleotide excision repair (NER). Single nucleotide polymorphisms (SNP) in XPC gene may affect DNA repairing capacity and genetic susceptibility to cancer. This study was to investigate the correlation of XPC exon 8 Ala499Val and exon 15 Lys939Gln SNPs to the susceptibility of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population at a high incidence region of Hebei Province. METHODS: XPC exon 8 Ala499Val and exon 15 Lys939Gln SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis in 327 ESCC patients, 253 GCA patients, and 612 healthy controls. RESULTS: The number of the subjects with family history of upper gastrointestinal cancer (UGIC) was significantly higher in ESCC and GCA groups than in control group. Family history of UGIC may increase the risk of developing ESCC and GCA [age and gender adjusted odds ratio (OR) =1.76 and 1.77, 95% confidence interval (CI) = 1.34-2.32 and 1.31-2.39]. The overall allelotype and genotype distributions of XPC exon 8 Ala499Val in ESCC patients were not significantly different from those in healthy controls (P>0.05). T allelotype frequency of XPC exon 8 in GCA patients was 26.5%, which was significantly lower than that in healthy controls (Chi2=6.12, P=0.01). The C/T genotype frequencies of XPC exon 8 in GCA patients and healthy controls were 35.6% and 46.1% respectively. Compared with individuals with C/C genotype, individuals with C/T genotype had significantly lower risk in developing GCA (OR=0.62, 95% CI=0.45-0.84). When stratified for smoking status and family history of UGIC, compared with individuals with C/C genotype, individuals with C/T genotype in smoker group and in the group without family history of UGIC had lower risk in developing GCA (OR=0.57, 95% CI=0.36-0.91 and 0.37-0.88). The overall allelotype and genotype distributions of XPC exon 15 Lys939Gln in ESCC and GCA patients were not significantly different from those in healthy controls (P>0.05). When stratified for smoking status and family history of UGIC, compared with individuals with A/A genotype, individuals in non-smoker group with C/C genotype had higher risk in developing ESCC (OR=2.05, 95% CI=1.15-3.66). The haplotype distribution of ESCC patients was not significantly different from that of healthy controls (P>0.05), while the haplotype distribution of GCA patients was significantly different from that of healthy controls (P=0.02). Compared with A/T haplotype, A/C and C/C haplotypes significantly increased the risk of developing GCA (OR=1.35 and 1.46, 95% CI=1.01-1.81 and 1.06-2.00). CONCLUSIONS: In the high incidence region of Hebei Province, C/T genotype of XPC exon 8 may decrease the risk of developing GCA. Lys939Gln SNP in exon 15 may have no influence on the risk of ESCC and GCA, but when stratified for smoking status, C/C genotype of XPC exon 15 may increase the risk of developing ESCC in non-smoking population. While A/C and C/C haplotypes may increase the risk of developing GCA.