Da-Peng Ding

TRPM8 promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3β pathway

Breast cancer already taken the first place of incidence in Chinese female cancer patients. TRPM8 is found to be over-expressed in breast cancer, but whether it promotes breast cancer aggressiveness remains unknown. In our study, TRPM8 was identified highly expressing in all the tested breast cancer cell lines including MCF-7, T47D, MDA-MB-231, BT549, SKBR3 and ZR-75-30, while it just could be detected in MCF-10A, the normal breast epithelial cell. Then four pairs of clinical samples were analyzed using Western blotting and the result showed that TRPM8 expression is higher in tumor tissues than in adjacent nontumor tissues. Subsequently, we established TRPM8 high-expressing MCF-7 cell line and TRPM8 knockout MDA-MB-231 cell line to explore expression status of cancer-related proteins. The Western blotting and immunofluorescence analysis outcomes demonstrated that TRPM8 might influence cancer cell metastasis by regulating the EMT phenotype via activating AKT/GSK-3β pathway, and the hypothesis had been supported by cell function tests. All the results demonstrated that TRPM8 significantly up-expressed in breast cancer cells and promoted their metastasis by regulating EMT via activating AKT/GSK-3β pathway, indicating TRPM8 gets the prospects of to be developed as medication or diagnostic indicator to be applied in clinical work.

Association between the XRCC3 T241M polymorphism and risk of cancer: evidence from 157 case-control studies.

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR]=1.07, 95% confidence interval [CI]=1.00-1.13; recessive model: OR=1.15, 95% CI=1.08-1.23; additive model: OR=1.17, 95% CI=1.08-1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC3 polymorphism in cancer development.

Lack of association between XPG Asp1104His and XPF Arg415Gln polymorphism and breast cancer risk: a meta-analysis of case–control studies

The xeroderma pigmentosum group G (XPG or ERCC5) and group F (XPF or ERCC4) play an important role in DNA repair, and produce dual incision 3′ and 5′ to the damaged nucleotide fragment. Several polymorphisms in the XPF and XPG gene have been described, including the commonly occurring Asp1104His in XPG and Arg415Gln in XPF. The published data on the association between these polymorphisms and breast cancer remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 17 studies were identified to the meta-analysis, including 5,235 cases and 5,685 controls for XPG Asp1104His (from ten studies) and 3,910 cases and 3,985 controls for XPF Arg415Gln (from seven studies). Overall, no significantly elevated breast cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (for XPG Asp1104His Asp/His vs. Asp/Asp: OR 1.02, 95% CI 0.94–1.11; His/His vs. Asp/Asp: OR 0.96, 95% CI 0.83–1.11; dominant model: OR 1.01, 95% CI 0.94–1.09; and for XPF Arg415Gln Arg/Gln vs. Arg/Arg: OR 1.00, 95% CI 0.89–1.12; Gln/Gln vs. Arg/Arg: OR 2.40, 95% CI 0.62–9.22; dominant model: OR 1.03, 95% CI 0.90–1.18). In stratified analyses, we observed an overall OR of 5.20 (95% CI 2.08–12.95) for breast cancer developing risk in the Caucasian ethnicity, comparing Gln/Gln type to wild-type Arg/Arg for Arg415Gln polymorphism. In conclusion, this meta-analysis suggests that XPG Asp1104His polymorphism is not associated with increased breast cancer risk, and XPF Arg415Gln may be a low-penetrant risk factor in the Caucasian ethnicity for developing breast cancer.

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.

Lack of association between XPD Lys751Gln and Asp312Asn polymorphisms and colorectal cancer risk: a meta-analysis of case–control studies

PurposeThe published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln and Asp312Asn polymorphisms and colorectal cancer remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship.Materials and methodsA comprehensive literature search was conducted to identify all case–control studies of Lys751Gln and Asp312Asn polymorphisms on the susceptibility of different tumor site of colorectal cancer (colon, rectum, and colon/rectum cancer). A total of 22 eligible studies were selected for this meta-analysis, including 3,042 cases and 4,627 controls for Lys751Gln and 1,581 cases and 2,846 controls for Asp312Asn.ResultsOverall, no significantly elevated colorectal cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (for Lys751Gln polymorphism: Lys/Gln vs. Lys/Lys, OR = 1.01, 95% CI = 0.90–1.14; Gln/Gln vs. Lys/Lys, OR = 1.04, 95% CI = 0.85–1.26; dominant model, OR = 1.03, 95% CI = 0.93–1.15; recessive model, OR = 1.04, 95% CI = 0.87–1.25; and for Asp312Asn polymorphism: Asp/Asn vs. Asp/Asp, OR = 1.11, 95% CI = 0.91–1.35; Asn/Asn vs. Asp/Asp, OR = 1.13, 95% CI = 0.87–1.47; dominant model, OR = 1.09, 95% CI = 0.94–1.26; recessive model, OR = 1.11, 95% CI = 0.88–1.41). And for the additive model, individuals carrying the 751Gln or 312Asn allele were not significantly associated with increased risk to colorectal cancer (OR = 1.02, 95% CI = 0.94–1.11, OR = 1.07, 95% CI = 0.95–1.20).ConclusionThis meta-analysis suggests that XPD Lys751Gln and Asp312Asn polymorphisms may not be associated with colorectal cancer development.

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.

N-Acetyltransferase Polymorphism and Risk of Colorectal Adenoma and Cancer: A Pooled Analysis of Variations from 59 Studies

Background There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship. Methods/Principal Findings A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk (OR 0.99, 95% CI 0.91–1.07). We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC (OR 1.07, 95% CI 1.01–1.13). There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk (NAT1: OR 1.14, 95% CI 0.99–1.29; NAT2: OR 0.94, 95% CI 0.86–1.03). Conclusion This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk.

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.

Lack of association of ADH1C genotype with breast cancer susceptibility in Caucasian population: A pooled analysis of case–control studies

PURPOSE Recent epidemiological studies demonstrated that alcohol dehydrogenase 1C (ADH1C) alleles that result in acetaldehyde accumulation in the cells can enhance a drinkers risk of developing alcohol related cancer in a variety of tissues. The published data on the association between ADH1C alleles and breast cancer occurrence in Caucasians have led to in contradictory results. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. METHODS A total of 12 studies were identified to the meta-analysis, including 6159 cases and 5732 controls from Caucasians. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with ADH1C genotype was estimated. RESULTS Overall, no significantly elevated breast cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (ADH1C(1-2) vs. ADH1C(2-2): OR 1.07, 95% CI 0.97-1.19; ADH1C(1-1) vs. ADH1C(2-2): OR 1.16, 95% CI 0.94-1.43; dominant model: OR 1.07, 95% CI 0.97-1.18; recessive model: OR 1.06, 95% CI 0.93-1.20). There was no evidence for the association between ADH1C genotype and breast cancer risk in subgroup analyses based on design of experiment and menopausal status. And for the additive model, individuals carrying the ADH1C*(1) allele were not significantly associated with increased risk to breast cancer (OR 1.01, 95% CI 0.97-1.06). CONCLUSION This meta-analysis suggests that ADH1C polymorphism may not be associated with breast cancer development in Caucasians. And larger scale primary studies are required to further evaluate the interaction of ADH1C polymorphism and breast cancer risk in specific populations.

Lack of association between hOGG1 Ser326Cys polymorphism and breast cancer susceptibility in European population

Recently, we read with great interest the article ‘‘The hOGG1 Ser326Cys polymorphism and breast cancer risk: a meta-analysis’’ published online in August 2010 issue of ‘‘Breast Cancer Research and Treatment’’ [1]. The study of Yuan et al. performed a meta-analysis to make an estimation of the association between the DNA repair gene hOGG1 Ser326Cys polymorphism (rs1052133) and breast cancer susceptibility, and the results showed that individuals who carrying the hOGG1 326Cys allele did not have significantly increased risk of breast cancer compared with those carrying the 326Ser allele. However, in the stratified analysis by ethnicity, the meta-analysis showed the association between hOGG1 326Cys allele in the additive model, and breast cancer was significant in European subject (OR = 0.71, 95% CI = 0.51–0.98), and dominant genetic model (OR = 0.44, 95%CI = 0.25–0.77), and the 326Cys allele plays a protective effect on the carcinogenesis of breast cancer among them. Nevertheless, there are some comments we would like to raise. Using the same search strategy and end-of-search date as those of Yuan et al. [1], we have found that the data reported by Yuan et al. [1] for the study by Zhang et al. [2] do not seem in line with the data provided by Zhang et al. [2] in their original publication. The ethnicity of eligible sample (1,571 cases and 1,244 controls) reported by Yuan et al. [1] are the American population. And three other studies were involved in the European populations [3–5]. Interestingly enough, after carefully studying the data presented by Zhang et al. [2], we found that this study population was restricted to Caucasian women to limit heterogeneity, mostly of central European ancestry. And the data reported by Yuan et al. [1] for the study by Vogel et al. [5] is not included in the stratified analysis for the European population. Hence, the ongoing uncertainly still existed, and the conclusion by Yuan et al. [1] was not entirely credible. In light of the above, we have combined all of the studies for European population into a new meta-analysis, including four case–control studies as described by Yuan et al. [2–5]. Our pooled results indicate that the hOGG1 326Cys allele is not associated with breast cancer risk in European population (Ser/Cys vs. Ser/Ser: OR = 0.76, 95% CI = 0.54–1.07; Cys/Cys vs. Ser/Ser: OR = 0.85, 95% CI = 0.65–1.12; dominant model: OR = 0.78, 95% CI = 0.58–1.07; recessive model: OR = 0.96, 95% CI = 0.74–1.24). And for the additive model (326Cys allele vs. 326Ser allele), individuals carrying the 326Cys allele were not significantly associated with increased risk to breast cancer (OR = 0.93, 95% CI = 0.84–1.04). The meta-analysis was based on currently available evidence and was meant to accurately assess the relationship. We have also read with great interest the recent metaanalysis by Gu et al. [6], the study of Gu et al. [6] had eleven case–control studies, and the results suggest that no significant associations between the hOGG1 Ser326Cys Da-Peng Ding and Ying Zhang contributed equally to this study and should be considered as co-first authors.