[Show abstract][Hide abstract] ABSTRACT: Sineoculis homeobox homolog 1 (Six1), normally a developmentally restricted transcriptional regulator, is frequently dysregulated in mutiple cancers. Increasing evidences show that overexpression of Six1 plays a key role in tumorigenesis. However, the Six1 expression status and its relationship with the clinicopathological characteristics in prostate cancer were unclear. In this study, the mRNA and protein levels of Six1 in prostate cancer tissues and normal prostate tissues were evaluated. The clinicopathological significance of Six1 was investigated by immunohistochemistry (IHC) on a prostate cancer tissue microarray. The cut-off score for high expression of Six1 was determined by the receiver-operating characteristic (ROC) analysis. The correlation between Six1 protein expression and clinicopathological characteristics of prostate cancer was analyzed by Chi-square test. Increased expression of Six1 protein was observed in the majority of prostate cancer, compared with their paired adjacent normal prostate tissues. When Six1 high expression percentage was determined to be above 55 % (area under ROC curve = 0.881, P = 0.000), high expression of Six1 was observed in 55.6 % (80/144) of prostate cancer tissues and low expression of Six1 was observed in all normal prostate tissues by IHC. Increased expression of Six1 in patients was correlated with high histological grade (χ2 = 58.651, P = 0.00), advanced clinical stage (χ2 = 57.330, P = 0.000), high Gleason score (χ2 = 63.480, P = 0.000), high primary tumor grade (χ2 = 57.330, P = 0.000) and positive regional lymph node metastasis (χ2 = 19.294, P = 0.000). Furthermore, univariate and multivariate survival analysis suggested that Six1 was an independent prognostic indicator for overall survival (P < 0.05). This study suggests that Six1 could be served as an additional biomarker in identifying prostate cancer patients at risk of tumor progression, might potentially be used for predicting survival outcome of patients with prostate cancer.
Cancer Cell International 01/2015; 15(1):63. DOI:10.1186/s12935-015-0215-z · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excision repair crossing-complementing group 2 (ERCC2), also called xeroderma pigmentosum complementary group D (XPD), plays a crucial role in the nucleotide excision repair (NER) pathway. Previous epidemiological studies have reported associations between ERCC2 polymorphisms and non-Hodgkin lymphoma (NHL) risk, but the results have remained controversial.
We conducted this meta- analysis based on eligible case-control studies to investigate the role of two ERCC2 polymorphisms (Lys751Gln and Asp312Asn) in determining susceptibility to NHL. Ten case-control studies from several electronic databases were included in our study up to August 14, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models to estimate the association strength.
The combined results based on all studies did not show any association between Lys751Gln/Asp312Asn polymorphisms and NHL risk for all genetic models. Stratified analyses by histological subtype and ethnicity did not indicate any significant association between Lys751Gln polymorphism and NHL risk. However, a significant reduced risk of NHL was found among population-based studies (Lys/Gln versus Lys/Lys: OR=0.87, 95% CI=0.77-0.99, P=0.037) but not hospital-based studies. As for Asp312Asn polymorphism, there was no evidence for the association between this polymorphism and the risk of NHL in all subgroup analyses.
This meta-analysis suggests that there may be no association between Lys751Gln/Asp312Asn polymorphism and the risk of NHL and its two subtypes, whereas ERCC2 Lys751Gln heterozygote genotype may provide protective effects against the risk of NHL in population-based studies. Therefore, large-scale and well-designed studies are needed to clarify the effects of haplotypes, gene-gene, and gene-environment interactions on these polymorphisms and the risk of NHL and its different histological subtypes in an ethnicity specific population.
Asian Pacific journal of cancer prevention: APJCP 11/2014; 15(21):9347-53. DOI:10.7314/APJCP.2014.15.21.9347 · 2.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Three extensively investigated polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) in the X-ray repair cross-complementing group 1 (XRCC1) gene have been implicated in risk for glioma. However, the results from different studies remain inconsistent. To clarify these conflicts, we performed a quantitative synthesis of the evidence to elucidate these associations in the Chinese population.
Data were extracted from PubMed and EMBASE, with the last search up to August 21, 2014. Meta-analysis was performed by critically reviewing 8 studies for Arg399Gln (3062 cases and 3362 controls), 8 studies for Arg194Trp (3419 cases and 3680 controls), and 5 studies for Arg280His (2234 cases and 2380 controls). All of the statistical analyses were performed using the software program, STATA (version 11.0).
Our analysis suggested that both Arg399Gln and Arg194Trp polymorphisms were significantly associated with increased risk of glioma (for Arg399Gln polymorphism: Gln/Gln vs. Arg/Arg, OR = 1.82, 95% CI = 1.46–2.27, P = 0.000; Arg/Gln vs. Arg/Arg, OR = 1.25, 95% CI = 1.10–1.42, P = 0.001 and for Arg194Trp polymorphism: recessive model, OR = 1.78, 95% CI = 1.44–2.19, P = 0.000), whereas the Arg280His polymorphism had no influence on the susceptibility to glioma in a Chinese population.
This meta-analysis suggests that there may be no association between the Arg280His polymorphism and glioma risk, whereas the Arg399Gln/Arg194Trp polymorphisms may contribute to genetic susceptibility to glioma in the Chinese population. Nevertheless, large-scale, well-designed and population-based studies are needed to further evaluate gene-gene and gene–environment interactions, as well as to measure the combined effects of these XRCC1 variants on glioma risk.
PLoS ONE 11/2014; 9(11):e111981. DOI:10.1371/journal.pone.0111981 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Pin2/TRF1 binding protein X1 (PinX1) has been identified as an endogenous telomerase inhibitor and a major haploinsufficient tumor suppressor gene. Increasing evidence suggests that reduced expression of PinX1 plays a key role in tumorigenesis. However, the PinX1 expression status and its correlation with the clinicopathological features in prostate cancer (PCa) have not been investigated.
PinX1 mRNA and protein expression in PCa and adjacent normal prostate tissues were evaluated by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The clinicopathological significance of PinX1 was investigated by immunohistochemistry (IHC) analysis on a PCa tissue microarray (TMA). The cut-off score for positive expression of PinX1 was determined by the receiver operating characteristic (ROC) analysis. The correlation between PinX1 expression and clinicopathological features of PCa was analyzed by Chi-square test.
Reduced expression of PinX1 mRNA and protein was observed in the majority of PCa, compared with their paired adjacent normal prostate tissues. When PinX1 positive expression percentage was determined to be above 60% (area under ROC curve = 0.833, P = 0.000), positive expression of PinX1 was observed in 100% (8/8) of normal prostate tissues and 32.5% (13/40) of PCa tissues by IHC. Reduced expression of PinX1 in patients was correlated with advanced clinical stage (χ2 = 10.230, p = 0.017), high Gleason score (χ2 = 4.019, p = 0.045), positive regional lymph node metastasis (χ2 = 10.852, p = 0.004) and distant metastasis (χ2 = 7.965, p = 0.005).
Our findings suggest that reduced expression of PinX1 is correlates to progressive features in patients with PCa and may serve as a potential marker for diagnosis.
Cancer Cell International 06/2014; 14(1):46. DOI:10.1186/1475-2867-14-46 · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As a major tumor suppressor gene, the role of PinX1 in breast cancer and its molecular mechanism remain unclear. In this study, overexpression of PinX1 was generated in 3 breast cancer cell lines, and knockdown of PinX1 was performed in a nontumorigenic breast cell line. The regulation of PinX1 on cell proliferation and cell cycle was observed. A microarray-based lncRNA and mRNA expression profile screening was also performed. We found a lower growth rate, G0/G1 phase arrest, and S phase inhibition in the PinX1 overexpressed breast cancer cells, while a higher growth rate, decreased G0/G1 phase, and increased S phase rate in the PinX1 knocked-down nontumorigenic breast cell. A total of 977 mRNAs and 631 lncRNAs were identified as differentially expressed transcripts between PinX1 overexpressed and control MCF-7 cells. Further analysis identified the involvement of these mRNAs in 52 cancer related pathways and various other biological processes. 11 enhancer-like lncRNAs and 25 lincRNAs with their adjacent mRNA pairs were identified as coregulated transcripts. Our results confirmed the role of PinX1 as a major tumor suppressor gene in breast cancer cell lines and provided information for further research on the molecular mechanisms of PinX1 in tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: It is known that chemoresistance is a major cause of treatment failure in acute myeloid leukemia (AML). Substantial data indicate that the CD44 adhesion molecule is strongly expressed on AML blasts and that it can also inhibit apoptosis. Our study shows that drug resistance of the AML cell line HL60/ADM is due to overexpression of CD44. In an in vitro study, we knocked down CD44 in the HL60/ADM cell line using small interfering RNA (siRNA). Cell proliferation and the 50 % inhibitory concentrations (IC50) were determined by Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis and intracellular ADM accumulation were detected by flow cytometry. Expression of CD44, Bcl-2, c-Myc were assayed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The results indicate that the expression of CD44 in HL60/ADM cell line was much higher than in HL60 cell, and siRNA targeted CD44 (siRNA/CD44) could silence its expression in both mRNA and protein levels effectively. siRNA/CD44 substantially induces cell apoptosis, inhibits cell proliferation, enhances susceptibility to ADM and Ara-C, and at the same time increases intracellular ADM accumulation even reverses chemoresistance to ADM and Ara-C. Furthermore, by qRT-PCR and Western blot, we found that siRNA/CD44 decreases Bcl-2 and c-Myc synthesis. Our study provides a novel clue that CD44 plays a significant role in the chemoresistance of AML cells to Ara-C and ADM. Moreover, this provides a new direction to the approaches that combination therapy including targeting CD44 may overcome drug resistance and improve treatment effects.
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggest that ubiquitin-proteasome system (UPS) plays a key role in tumorigenesis. HERC4 is a recently identified ubiqutin ligase. However, the expression status and biological functions of HERC4 in cancers are not clearly.
We evaluated the HERC4 expression in breast cancer cell lines and breast tumor tissues by quantitative real-time PCR and western blot analysis. To investigate the clinicopathological significance of HERC4, immunohistochemistry analysis for HERC4 was performed on a tissue microarray including 13 benign fibroadenoma, 15 intraductal carcinoma, 120 histologically confirmed invasive ductal carcinoma. Receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off score for positive expression of HERC4, when HERC4 positive expression percentage was above 60%, tumor was defined as "positive".
HERC4 was up-regulated in breast cancer cell lines and breast tumor tissues compared to non-tumorigenic cell line and adjacent normal breast tissues. According to ROC analysis, HERC4 positive expression was detected in 1/16 (6.3%) of normal breast tissue, in 3/13 (23.1%) of fibroadenoma, in 6/15(40%) of intraductal carcinoma and 66/120 (55%) of invasive ductal carcinoma. Positive expression of HERC4 was positively correlated with pT status, pN status, clinical stage and histological grade of patients with invasive ductal carcinoma (p < 0.05).
Our findings suggest that HERC4 was a significant diagnostic marker for invasive ductal carcinoma of the breast.
Cancer Cell International 11/2013; 13(1):113. DOI:10.1186/1475-2867-13-113 · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The multidrug resistance (MDR) 1 gene encodes a 170-kDa membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by the way of an ATP-dependent cellular efflux mechanism. Three polymorphisms of MDR1, 3435C > T located in exon 26, 1236C > T in exon 12 and 2677G > T/A in exon 21 were the most extensively studied and were identified functionally important and ethnically diverse mapping to the gene region. Considering the potential influence of altering MDR1 activity, it is plausible that MDR1 polymorphisms might play a role in the development of cancer. Although the effects of MDR1 polymorphisms on susceptibility to human cancer have been investigated in many studies, the results still remain conflicting. METHODS: To resolve these conflicts, we performed a quantitative synthesis of the association between these three polymorphisms and cancer risk, including 52 studies (15789 cases and 20274 controls) for 3435C > T polymorphism, 10 studies (2101 cases and 2842 controls) for 1236C > T polymorphism and 18 studies (3585 cases and 4351 controls) for 2677G > T/A polymorphism. RESULTS: The stratified analyses for 3435C > T polymorphism, individuals with T-allele in 3435C > T had significantly higher ALL risks (TT versus CC: OR =1.286, 95% CI =1.123-1.474); significantly elevated risks were observed among Caucasian populations (TT versus CC: OR =1.276, 95% CI =1.112-1.464). When restricting the analysis to the source of controls, we found that HB (hospital-based) genetic models had higher risks (TT versus CC: OR =1.307, 95% CI =1.046-1.632), as well as in PB (population-based) genetic models (TT versus CC: OR =1.294, 95% CI =1.079-1.55).The T/A-allele frequency of 2677G > T/A polymorphism was associated with higher risk of cancer (TT + TA + AA vs. GG: OR =1.348, 95% CI =1.031-1.762), significantly elevated risks were observed among Asian populations (TT + TA + AA vs. GG: OR =1.642, 95% CI =1.340-2.012), and elevated risks could be associated with PB models (TT + TA + AA vs. GG: OR =1.641, 95% CI =1.018-2.646). CONCLUSIONS: Our meta-analysis suggested that 3435C > T polymorphism and 2677G > T/A polymorphism were associated with cancer risk when all studies were pooled together, while 1236C > T polymorphism not.
Cancer Cell International 05/2013; 13(1):46. DOI:10.1186/1475-2867-13-46 · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the role of aquaporin-1 (AQP1) gene in erythroid differentiation of erythroleukemia K562 cells induced by retinoic acid (RA).
K562 cells were cultured in the presence of 1 µmol/L RA for varying lengths of time, and γ-globin mRNA expression and hemoglobin content in the cells were detected by real-time PCR (RT-PCR) and ultraviolet spectrophotometry, respectively, to evaluate the erythroid differentiation of K562 cells. RT-PCR and Western blotting were used to examine AQP1 expression in the cells following RA treatment. A retroviral expression vector of AQP1 small interfering RNA (pSUPER-retro-puro-shAQP1) was constructed and transfected into K562 cells to establish a K562 cell line with stable AQP1 down-regulation (K562-shAQP1), in which the changes in γ-globin and hemoglobin expressions after RA treatment were detected.
RA treatment significantly increased γ-globin and hemoglobin expressions in K562 cells (P<0.01), causing also significantly enhanced AQP1 mRNA and protein expressions over time (P<0.01). Transfection with the recombinant plasmids pSuper-retro-puro-shAQP1 resulted in stable AQP1 suppression in K562 cells (P<0.01), which showed markedly reduced γ-globin and hemoglobin expressions after RA induction as compared to the control K562 cells (P<0.01).
K562 cells show a significant increase of AQP1 expression after RA-induced erythroid differentiation, and suppression of AQP1 expression can partially block the effect of RA, suggesting the important role of AQP1 in RA-induced erythroid differentiation of K562 cells.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University 12/2012; 32(12):1689-94.
[Show abstract][Hide abstract] ABSTRACT: Thymidylate synthase (TS) is an important enzyme involved in folate metabolism and catalyzes methylation of deoxyuridine monophosphate to deoxythymidine monophosphate, which is essential for DNA replication. Thymidylate synthase enhancer region (TSER) and TS1494del6, two functionally important and ethnically diverse polymorphisms mapping to its gene region, are the most extensively studied. Considering the potential influence of altering TS activity, it is plausible that TS polymorphisms might play a role in the development of cancer. Although the effects of TS polymorphisms on susceptibility to human cancer have been investigated in many studies, the results remain conflicting rather than conclusive. To resolve these conflicts, we performed a quantitative synthesis of the evidence on the association between these two polymorphisms and cancer risk, including 63 studies (19,707 cases and 27,398 controls) for TSER polymorphism and 39 studies (13,489 cases and 16,297 controls) for TS1494del6 polymorphism. Our meta-analysis suggested that these two polymorphisms are not associated with cancer risk when all studies were pooled together. In the stratified analyses, we found that individuals with 2R/2R genotype had a significantly higher cancer risks among Asians (2R/2R vs. 3R/3R: odds ratio [OR] = 1.24, 95% confidence interval (95% CI) = 1.05-1.45; recessive model: OR = 1.23, 95% CI = 1.05-1.44). Further analyses revealed that 2R/2R genotype was significantly associated with an increased risk of gastroesophageal cancer among Asians, whereas it might provide protecting effects against colorectal cancer risk in a dominant genetic model for Caucasians. Additionally, TS1494del6 polymorphism may contribute to genetic susceptibility of breast cancer among Asians.
International Journal of Cancer 11/2012; 131(9):2103-16. DOI:10.1002/ijc.27465 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. Epidemiological studies have evaluated the association between SHBG Asp327Asn polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 10 studies were identified for the meta-analysis, including 10,454 cases and 13,111 controls for SHBG Asp327Asn polymorphism. When all studies were pooled into the meta-analysis, there was no evidence for significant association between SHBG Asp327Asn polymorphism and breast cancer risk (for Asn/Asn vs. Asp/Asp: OR = 1.20, 95 % CI = 0.94-1.55; for Asp/Asn vs. Asp/Asp: OR = 0.94, 95 % CI = 0.87-1.01; for dominant model: OR = 0.95, 95 % CI = 0.90-1.02; for recessive model: OR = 1.22, 95 % CI = 0.95-1.57). In the subgroup analyses by ethnicity, menopausal status, and source of controls, no significant associations were found in all genetic models. Interestingly, further analyses stratified by menopausal status in different ethnicities revealed that this polymorphism might provide protective effects against breast cancer risk in postmenopausal Asian women (for dominant model: OR = 0.83, 95 % CI = 0.70-0.97). Sensitivity analyses were performed by sequential removal of individual studies and cumulative statistics have showed combined ORs were not materially altered by any individual study under all comparisons. In summary, this meta-analysis suggests that SHBG Asp327Asn polymorphism is not associated with breast cancer risk overall, while it might be an important genetic susceptibility factor in postmenopausal Asian women for developing breast cancer. Larger and well-designed studies are warranted to confirm our findings in the future.
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies have evaluated the association between polymorphic sites in the thymidylate synthase (TYMS) gene and non-Hodgkin lymphoma (NHL) risk, but the results remain controversial. Here we performed a meta-analysis to estimate the relationship between TYMS polymorphisms and the risk of NHL and two of its subtypes from all nine published case-control studies. Our meta-analysis suggested that both 1053C > T and IVS6-68C >T polymorphisms were significantly associated with decreased risks of NHL among Caucasians (for 1053C > T: TT vs. CC, odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.64-0.95; recessive model, OR = 0.81, 95% CI = 0.67-0.98 and for IVS6 - 68C > T: TT vs. CC, OR = 0.61, 95% CI = 0.40-0.92; recessive model, OR = 0.63, 95% CI = 0.42-0.93), whereas the TSER, 1122A > G and 1494del6 polymorphisms had no influence on the susceptibility to NHL. Further analysis revealed that the T allele of the 1053C > T polymorphism might provide protective effects in Caucasians against the risk of NHL (OR = 0.90, 95% CI = 0.82-0.98) and follicular lymphoma (FL) (OR = 0.81, 95% CI = 0.71-0.93), but not diffuse large B-cell lymphoma (DLBCL). Additionally, the IVS6 - 68C > T variant homozygote genotype was significantly associated with reduced risks for DLBCL (TT vs. CC: OR = 0.51, 95% CI = 0.28-0.94; recessive model: OR = 0.53, 95% CI = 0.29-0.96), but not FL. However, individuals carrying the T allele of the IVS6 - 68C > T polymorphism were not significantly associated with reduced risks for DLBCL and FL.
[Show abstract][Hide abstract] ABSTRACT: The BRCA1-associated RING domain (BARD1) gene has been identified as a high-penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. Some association studies suggested that the BRAD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the results remain conflicting rather than conclusive. In order to derive a more precise estimation of the relationship, this meta-analysis was performed.
Eligible studies were identified by searching several databases for relevant reports published before March 2011. In total, 14 studies (11,870 cases and 7,687 controls) were included in the present meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with Cys557Ser carrier was estimated.
The carrier frequency of the Cys557Ser mutation was 3.85% (457/11,870) in patients with breast cancer and 3.29% (253/7,687) in healthy controls. When all studies were pooled into the meta-analysis, there was no evidence for significant association between Cys557Ser mutation and breast cancer risk (OR 1.14, 95% CI 0.94-1.34). In the subgroup analyses by design of experiment and family history with BRCA1/2 status (unselected cases, family history with non-BRCA1/2 cases, and family history with BRCA1/2-positive cases), no significant associations were found in any subgroup of population.
This meta-analysis strongly suggests that BARD1 Cys557Ser mutation is not associated with increased breast cancer risk.
Journal of Cancer Research and Clinical Oncology 08/2011; 137(10):1463-8. DOI:10.1007/s00432-011-1006-0 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism and esophageal cancer (EC) remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A comprehensive literature search was conducted to identify all case-control studies of Lys751Gln polymorphism and risk for two main types of EC: esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC). A total of 12 studies were identified to the meta-analysis, including 2,575 cases (1,294 ESCC and 1,281 EADC) and 4,951 controls (1,891 ESCC and 3,060 EADC). Random-effects or fix-effects model was used according to between-study heterogeneity. The odds ratio (OR) for the variant homozygous genotype Gln/Gln of the Lys751Gln polymorphism, compared with the wild type homozygote Lys/Lys, was 1.26, with 95% confidence interval (95% CI) 1.02-1.56, for EADC risk without between-study heterogeneity. When stratified by ethnicity, statistically significantly elevated risk was found among Chinese (Gln/Gln vs. Lys/Lys: OR 2.45, 95% CI = 1.10-5.44). However, no significant associations were found between XPD Lys751Gln polymorphism and EC risk when all studies pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR 1.07, 95% CI = 0.88-1.28; Gln/Gln vs.us Lys/Lys: OR 1.25, 95% CI = 0.92-1.71; dominant model: OR 1.09, 95% CI = 0.90-1.33). In conclusion, this meta-analysis suggests that the Lys751Gln genetic polymorphism may be a potential biomarker of EC susceptibility in Chinese populations. And a study with the larger sample size is needed to further evaluate gene-environment interaction on XPD Lys751Gln polymorphism and EC risk.