Hai-Lang Yu

Anti‐miR‐155 oligonucleotide enhances chemosensitivity of U251 cell to taxol by inducing apoptosis

The oncogene, microRNA‐155, is significantly elevated in GBM (glioblastoma multiforme), regulating multiple genes associated with cancer cell proliferation, apoptosis and invasiveness. Thus, miR‐155 can theoretically become a target for enhancement of the chemotherapy in cancer. Down‐regulating miR‐155 to enhance the effect of taxol has not been studied in human GBM. Human GBM U251 cells were treated with taxol and the miR‐155 inhibitor alone or in combination. IC50 values were dramatically decreased in cells treated with miR‐155 inhibitor combined with taxol, to a greater extent than those treated with taxol alone. Furthermore, the miR‐155 inhibitor significantly enhanced apoptosis in U251 cells. The data suggest that miR‐155 blockage increased the chemosensitivity to taxol in GBM cells, making combined treatment an effective therapeutic strategy for controlling the growth by inhibiting EAG1 expression.

Genetic variation of XPA gene and risk of cancer: A systematic review and pooled analysis

XPA, a zinc‐finger DNA‐binding protein, play an important role in both global genome and transcription‐coupled repair pathways. XPA −4G>A polymorphism was identified in the 5′ noncoding region, located four nucleotides upstream of the ATG start codon. Previous studies have shown that this polymorphism may affect mRNA tertiary structure and stability and play a role in susceptibility to cancer. However, the results remained controversial. To derive a more precise estimation of association between this polymorphism and risk of different types of cancer, we performed a meta‐analysis based on 36 case–control or case–cohort studies, including a total of 11,700 cases and 15,033 controls. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, no significantly elevated cancer risk was found in all genetic models when eligible studies were pooled into the meta‐analysis. In the stratified analyses, we found that individuals with A‐allele had a higher risk of lung cancer (AA versus GG: OR = 1.25, 95% CI = 1.09–1.43; recessive model: OR = 1.31, 95% CI = 1.16–1.48). When stratified by ethnicity, significantly elevated risks were observed among Asian populations (AA versus GG: OR = 1.31, 95% CI = 1.01–1.70; dominant model: OR = 1.14, 95% CI = 1.00–1.30). This meta‐analysis suggests that XPA −4G>A polymorphism is associated with increased lung cancer risk and may be a low‐penetrant risk factor in Asian ethnicity for cancer development.

The association between two polymorphisms in the TS gene and risk of cancer: A systematic review and pooled analysis

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.

Lack of association between BARD1 Cys557Ser variant and breast cancer risk: a meta-analysis of 11,870 cases and 7,687 controls.

PurposeThe 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.MethodsEligible 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.ResultsThe 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.ConclusionsThis meta-analysis strongly suggests that BARD1 Cys557Ser mutation is not associated with increased breast cancer risk.

MiR-519d facilitates the progression and metastasis of cervical cancer through direct targeting Smad7

BackgroundMicroRNAs (miRNAs) play pivotal roles in the development of various cancer types, including cervical cancer.Methods and resultsIn this study, we showed that miR-519d, a miRNA within the chromosome 19 miRNA cluster, was significantly upregulated in cervical cancer tissues, compared with non-tumorous cervical samples. Suppression of miR-519d markedly attenuated the migration and invasion of HeLa and SiHa cervical cancer cells. Additionally, miR-519d inhibited the apoptosis of cervical cancer cells, and the proliferation of cervical cancer cells was also affected following transfection of miR-519d inhibitor. Moreover, we identified Smad7 to be a novel target of miR-519d in cervical cancer cells. MiR-519d matched the 3′-UTR of Smad7 mRNA. Transfection with miR-519d mimics led to apparent downregulation of Smad7 both at the mRNA and protein levels. Luciferase reporter analysis revealed that miR-519d reduced the luciferase activity of Smad7 mRNA 3′-UTR through matching site-dependent manner. And more notably, suppression of Smad7 remarkably restored the migration and invasion of miR-519d-depleted cervical cancer cells.ConclusionTaken together, these findings implicated that miR-519d promoted the progression and metastasis of cervical cancer through targeting Smad7.

Association between APE1 Asp148Glu polymorphism and the risk of urinary cancers: a meta-analysis of 18 case–control studies

Background Several observational studies suggested that APE1 Asp148Glu was significantly associated with urinary cancers; however, the results of published studies are inconsistent. Materials and methods The PubMed and EMBASE were searched for case–control studies regarding the association between Asp148Glu and the risk of urinary cancers with a time limit of September 12, 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between Asp148Glu and the risk of developing prostate cancer, kidney cancer, bladder cancer, as well as all urinary cancers combined. Results A total of 18 case–control studies were included in the analysis. Our meta-analysis revealed that the inheritance of at least one APE1 148Glu among Asian men was associated with a 1.26-fold increase in the risk of developing urinary cancers. Meanwhile, APE1 Asp148Glu was significantly associated with the risk of prostate cancer. However, there were no significant relationships between the APE1 SNP (single nucleotide polymorphism) and all urinary cancers combined and bladder cancer and kidney cancer among the men of Caucasian/Asian/African descent or all racial/ethnic groups combined. When stratified by the quality score, no significant association was found in high-quality studies (score ≥7), but a significant increased risk of urinary cancers was observed in lower quality studies (score <7) (dominant model: OR=1.27, 95% CI=1.11–1.45). Conclusion Our meta-analysis suggests that APE1 Asp148Glu was not associated with the risk of urinary cancers but might increase the risk of urinary cancers among Asians. Stratification by cancer type identified a significant association of Asp148Glu with prostate cancer.

Association between polymorphic sites in thymidylate synthase gene and risk of non-Hodgkin lymphoma: a systematic review and pooled analysis

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.

Comprehensive Assessment of Associations between ERCC2 Lys751Gln/Asp312Asn Polymorphisms and Risk of Non-Hodgkin Lymphoma

BACKGROUND 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Thymidylate synthase polymorphisms and hematological cancer risk: evidence needs further clarification.

Recently, we read with great interest the article “ Th ymidylate synthase polymorphisms and hematological cancer risk: a meta-analysis ” when it was published online in Leukemia and Lymphoma [1], which reached important conclusions about the association between two polymorphisms (TSER and 1494del6) in the thymidylate synthase (TYMS) gene and hematological cancer risk. Th rough quantitative analysis, this meta-analysis suggests that the TSER polymorphism may contribute to susceptibility to acute lymphoblastic leukemia (ALL) in children (3R/3R vs. 2R/2R: odds ratio [OR] 1.46, 95% confi dence interval [CI] 1.03 – 2.06) and non-Hodgkin lymphoma (NHL) in Caucasians (2R/3R vs. 2R/2R: OR 1.31, 95% CI 1.10 – 1.56) but protection from ALL risk in adults (2R/3R vs. 2R/2R: OR 0.64, 95% CI 0.43 – 0.97). In addition, the results show that the TS and 3′ -untranslated region (UTR) 1494del6 polymorphism may have a protective effect on