N6-methyladenosine RNA modification in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, influencing numerous regulatory axes and extrahepatic vital organs. The molecular mechanisms that lead to the progression of NAFLD remain unclear and knowledge on the pathways causing hepatocellular damage followed by lipid accumulation is limited. Recently, a number of studies have shown that mRNA N6-methyladenosine (m6A) modification contributes to the progression of NAFLD. In this review, we summarize current knowledge on m6A modification in the metabolic processes associated with NAFLD and discuss the challenges of and prospects for therapeutic avenues based on m6A regulation for the treatment of liver disease.

Glutamine metabolism in breast cancer and possible therapeutic targets.

Cancer is characterized by metabolic reprogramming, which is a hot topic in tumor treatment research. Cancer cells alter metabolic pathways to promote their growth, and the common purpose of these altered metabolic pathways is to adapt the metabolic state to the uncontrolled proliferation of cancer cells. Most cancer cells in a state of nonhypoxia will increase the uptake of glucose and produce lactate, called the Warburg effect. Increased glucose consumption is used as a carbon source to support cell proliferation, including nucleotide, lipid and protein synthesis. In the Warburg effect, pyruvate dehydrogenase activity decreases, thereby disrupting the TCA cycle. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for the reduction in oxidative phosphorylation pathways in cancer cells caused by the Warburg effect. In human plasma, glutamine is the most abundant amino acid. Normal cells produce glutamine via glutamine synthase (GLS), but the glutamine synthesized by tumor cells is insufficient to meet their high growth needs, resulting in a "glutamine-dependent phenomenon." Most cancers have an increased glutamine demand, including breast cancer. Metabolic reprogramming not only enables tumor cells to maintain the reduction-oxidation (redox) balance and commit resources to biosynthesis but also establishes heterogeneous metabolic phenotypes of tumor cells that are distinct from those of nontumor cells. Thus, targeting the metabolic differences between tumor and nontumor cells may be a promising and novel anticancer strategy. Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. In this review, the latest discoveries of breast cancer and glutamine metabolism are discussed, novel treatment methods based on amino acid transporters and glutaminase are discussed, and the relationship between glutamine metabolism and breast cancer metastasis, drug resistance, tumor immunity and ferroptosis are explained, which provides new ideas for the clinical treatment of breast cancer.

N6-methyladenosine RNA modification in PD-1/PD-L1: Novel implications for immunotherapy.

Cancer immunotherapy has been shown to achieve significant antitumor effects in a variety of malignancies. Out of all the immune checkpoint molecules, PD-1/PD-L1 inhibitor therapy has achieved great success. However, only some cancer patients benefit from this treatment strategy owing to drug resistance. Therefore, identifying the underlying modulators of the PD-1/PD-L1 pathway to completely comprehend the mechanisms of anti-PD-1/PD-L1 treatment is crucially important. Recent research has validated that m6A modification plays a critical role in the PD-1/PD-L1 axis, thus regulating the immune response and immunotherapy strategies. In this review, we summarized the latest research on the regulation of m6A modification in PD-1/PD-L1 pathways in cancer proliferation, invasion, and prognosis based on different kinds of cancers and discussed the possible mechanisms. We also reviewed m6A-associated lncRNAs in the regulation of the PD-1/PD-L1 pathway. More importantly, we outlined the influence of m6A modulation on anti-PD-1 therapy and m6A-related molecules that could predict the curative effect of anti-PD-1/PD-L1 therapy. Further studies exploring the definitive regulation of m6A on the PD1/PD-1 pathway and immunotherapy are needed, which may address some of the current limitations in immunotherapy.

A novel nine-microRNA-based model to improve prognosis prediction of renal cell carcinoma.

BACKGROUND: With the improved knowledge of disease biology and the introduction of immune checkpoints, there has been significant progress in treating renal cell carcinoma (RCC) patients. Individual treatment will differ according to risk stratification. As the clinical course varies in RCC, it has developed different predictive models for assessing patient's individual risk. However, among other prognostic scores, no transparent preference model was given. MicroRNA as a putative marker shown to have prognostic relevance in RCC, molecular analysis may provide an innovative benefit in the prophetic prediction and individual risk assessment. Therefore, this study aimed to establish a prognostic-related microRNA risk score model of RCC and further explore the relationship between the model and the immune microenvironment, immune infiltration, and immune checkpoints. This practical model has the potential to guide individualized surveillance protocols, patient counseling, and individualized treatment decision for RCC patients and facilitate to find more immunotherapy targets. METHODS: Downloaded data of RCC from the TCGA database for difference analysis and divided it into a training set and validation set. Then the prognostic genes were screened out by Cox and Lasso regression analysis. Multivariate Cox regression analysis was used to establish a predictive model that divided patients into high-risk and low-risk groups. The ENCORI online website and the results of the RCC difference analysis were used to search for hub genes of miRNA. Estimate package and TIMER database were used to evaluate the relationship between risk score and tumor immune microenvironment (TME) and immune infiltration. Based on Kaplan-Meier survival analysis, search for immune checkpoints related to the prognosis of RCC. RESULTS: There were nine miRNAs in the established model, with a concordance index of 0.702 and an area under the ROC curve of 0.701. Nine miRNAs were strongly correlated with the prognosis (P < 0.01), and those with high expression levels had a poor prognosis. We found a common target gene PDGFRA of hsa-miR-6718, hsa-miR-1269b and hsa-miR-374c, and five genes related to ICGs (KIR2DL3, TNFRSF4, LAG3, CD70 and TNFRSF9). The immune/stromal score, immune infiltration, and immune checkpoint genes of RCC were closely related to its prognosis and were positively associated with a risk score. CONCLUSIONS: The established nine-miRNAs prognostic model has the potential to facilitate prognostic prediction. Moreover, this model was closely related to the immune microenvironment, immune infiltration, and immune checkpoint genes of RCC.

A novel immune-related prognostic index for predicting breast cancer overall survival.

PURPOSE: To find immune-related genes with prognostic value in breast cancer, and construct a prognostic risk assessment model to make a more accurate assessment. Moreover, looking for potential immune markers for breast cancer immunotherapy. METHODS: The breast cancer (BC) data were retrieved from The Cancer Genome Atlas (TCGA) database as a training set. Through the Weighted gene co-expression network analysis (WGCNA), Kaplan-Meier (KM) analysis, lasso regression analysis and stepwise backward Cox regression analysis, screening for prognosis-related immune genes, a prognostic index was built, and external validation with two data sets of Gene Expression Omnibus (GEO) database was performed. Transcription factor (TF) regulatory network was constructed to identify key transcription factors that regulate prognostic immune genes. Gene set enrichment analysis (GSEA) was used to explore the signal pathways differences between high and low-risk groups, estimate package and TIMER database were used to evaluate the relationship between risk score and tumor immune microenvironment. RESULTS: We obtained 10 prognosis-related immune genes, and the index showed accurate prognostic value. We also identified 7 prognostic transcription factors. Multiple signaling pathways that inhibit tumor progression were enriched in the low-risk group, and risk score was significantly negatively related to the degree of immune infiltration and the expression level of immune checkpoint genes. CONCLUSION: We successfully constructed an independent prognostic index, which not only has a stronger predictive ability than the tumor pathological stage, but also can reflect the immune infiltration of breast cancer patients.

Linc-ROR promotes the progression of breast cancer and decreases the sensitivity to rapamycin through miR-194-3p targeting MECP2.

linc-ROR is reported to be a potential biomarker of breast cancer, but the detailed mechanism of linc-ROR-mediated breast cancer regulation has not been fully studied. We aimed to explore how linc-ROR affects proliferation, metastasis, and drug sensitivity in breast cancer. Cell lines in which linc-ROR was overexpressed or knocked down were constructed, and the cell proliferation, colony formation, cell migration, and invasion abilities of these lines were explored. A CCK-8 assay was performed to determine the sensitivity of the breast cancer cells to rapamycin. Next-generation sequencing was conducted to explore the detailed regulatory mechanism of linc-ROR; differentially expressed RNAs in the linc-ROR-overexpressing cell line compared with the negative control were screened out, and their target genes were chosen to perform Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, protein-protein interaction network analysis, and competing endogenous RNA (ceRNA) network analysis. The ceRNA mechanism of linc-ROR for miR-194-3p, which targets MECP2, was determined through dual-luciferase reporter assay, RT-qPCR, western blot, and rescue experiments. Finally, we found that linc-ROR was upregulated in breast tumor tissues. linc-ROR promoted the cell proliferation, colony formation, cell migration, and invasion of breast cancer and decreased the sensitivity of breast cancer cells to rapamycin. The overexpression of linc-ROR triggered changes in the whole transcriptome of breast cancer cells, and a total of 85 lncRNAs, 414 microRNAs, 490 mRNAs, and 92 circRNAs were differentially expressed in the linc-ROR-overexpressing cell line compared with the negative control. Through a series of bioinformatic analyses, the 'linc-ROR/miR-194-3p/MECP2' ceRNA regulatory axis was confirmed to be involved in the linc-ROR-mediated progression and drug sensitivity of breast cancer. In conclusion, linc-ROR serves as an onco-lncRNA in breast cancer and promotes the survival of breast cancer cells during rapamycin treatment by functioning as a ceRNA sponge for miR-194-3p, which targets MECP2.

Differential microRNA expression profiles determined by next-generation sequencing in three fulvestrant-resistant human breast cancer cell lines.

Fulvestrant resistance is a major clinical issue in the treatment of endocrine-based breast cancer. MicroRNAs (miRNAs) are known to serve an important role in tumor chemoresistance. In the present study, the association between miRNA expression profiles and fulvestrant resistance was investigated in human breast cancer cell lines. Three fulvestrant-resistant breast cancer cell lines, namely MCF-7-CC, MCF-7-TT and MCF-7-21, were established using the human breast cancer cell line MCF-7 as the parental cell line and fulvestrant as the screening drug in vitro. Next-generation sequencing was used to determine the miRNA expression profiles in these cell lines. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine the biological functions of differentially expressed miRNAs. In total, 1,536 miRNAs were detected in all the samples, including 1,240 known miRNAs and 296 predicted miRNAs. It was observed that the differential miRNA expression profiles varied among the three fulvestrant-resistant cell lines (MCF-7-CC, MCF-7-TT and MCF-7-21), and certain differentially expressed miRNAs were only detected in one or two of the cell lines. A total of 257 miRNAs that were differentially expressed between MCF-7-CC and MCF-7 cells were detected, among which 69 miRNAs were upregulated and 188 miRNAs were downregulated. In addition, 270 miRNAs with significantly different expression between MCF-7-TT and MCF-7 cells were observed, including 180 upregulated and 90 downregulated miRNAs. Between MCF-7-21 and MCF-7 cells, a total of 227 miRNAs were differentially expressed, among which 52 miRNAs were upregulated and 175 miRNAs were downregulated. The miRNAs that were differentially expressed in the three fulvestrant-resistant cell lines as compared with the parental MCF-7 cell line were primarily involved in the following biological processes: Biological regulation, extracellular matrix-receptor interaction, the Notch signaling pathway and focal adhesion. Taken together, the results suggested that miR-143, miR-145, miR-137, miR-424 and miR-21 may serve important roles in fulvestrant resistance in breast cancer. The study findings may provide a basis for further research on the treatment of fulvestrant-resistant breast cancer.

MicroRNA-99a Suppresses Breast Cancer Progression by Targeting FGFR3.

MicroRNAs have been implicated in acting as oncogenes or anti-oncogenes in breast cancer by regulating diverse cellular pathways. In the present study, we investigated the effects of miR-99a on cell biological processes in breast cancer. Breast cancer cells were transfected with a lentivirus that expressed miR-99a or a scramble control sequence. Functional experiments showed that miR-99a reduced breast cancer cell proliferation, invasion and migration. Tumor xenograft experiment suggested miR-99a overexpression inhibited breast cancer cell proliferation in vivo. The dual luciferase assay revealed that miR-99a directly targets FGFR3 by binding its 3' UTR in breast cancer. miR-99a was strongly down-regulated in breast tumor and FGFR3 was significantly up-regulated in breast tumor. FGFR3 silencing inhibited proliferation, migration and invasion of breast cancer cells. Deep sequencing indicated that miR-99a overexpression regulates multiple signaling pathways and triggers the alteration of the whole transcriptome. We constructed correlated expression networks based on circRNA/miRNA and lncRNA/miRNA competing endogenous RNAs regulation and miRNA-mRNA interaction, which provided new insights into the regulatory mechanism of miR-99a. In conclusion, these results suggest that the miR-99a/FGFR3 axis is an important tumor regulator in breast cancer and might have potential as a therapeutic target.

Differential microRNA profiles between fulvestrant-resistant and tamoxifen-resistant human breast cancer cells.

Increasing evidence has shown that the dysregulation of microRNAs (miRNAs) is associated with drug resistance. Fulvestrant and tamoxifen represent the major endocrine drugs for the treatment of breast cancer patients, and yet little is known about the biological mechanisms of acquiring resistance to fulvestrant and tamoxifen, let alone the differences between cell lines resistant to these two drugs. Exploration of the differential miRNA profiles between these two cell lines is a useful way to further clarify these resistance mechanisms. The fulvestrant-resistant cell line (MCF7-F) and the tamoxifen-resistant cell line (MCF7-T) were established from the drug-sensitive parental MCF7 cell line using a 21-day high-dose antiestrogen induction method. Differentially expressed miRNA profiles of MCF7-F and MCF7-T were detected using microarray; then, multiple bioinformatic analyses were carried out, including protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Compared with the parental MCF7 cell line, more miRNAs were found to be participating in the process of acquiring fulvestrant resistance than tamoxifen resistance. miR-4532, miR-486-5p, miR-138, miR-1228, and miR-3178 could be new targets for combating both fulvestrant resistance and tamoxifen resistance. miR-3188, miR-21, miR-149, and others may be associated with fulvestrant resistance, whereas miR-342 and miR-1226 may be associated with tamoxifen resistance in breast cancer cells. We found differential miRNA profiles between fulvestrant-resistant and tamoxifen-resistant breast cancer cells, but the definite mechanism involved in gaining resistance still needs further study.

Differential microRNA expression profiles in tamoxifen-resistant human breast cancer cell lines induced by two methods.

Tamoxifen (TAM) resistance has become a severe problem for endocrine therapy of breast cancer. The present study investigated the association between microRNA (miRNA) expression and TAM resistance in breast cancer. The TAM-resistant breast cancer MCF-7C and MCF-7T cell lines were established using the human breast cancer cell line MCF-7 as the parental cell line and 4-hydroxytamoxifen (OHT) as the screening drug in vitro. The MCF-7C cell line was established by dose stepwise induction beginning with a low concentration of OHT; the MCF-7T cell line was established by temporal stepwise induction beginning with a high concentration of OHT. Differential miRNA expression profiles between TAM-sensitive (MCF-7) and TAM-resistant (MCF-7C and MCF-7T) breast cancer cell lines were detected and analyzed using RNA sequencing technology. The results of western blot analysis indicated that the level of ERα protein expression in drug-resistant cells was significantly increased. A total of 1,646 miRNAs were detected in all samples, including 1,376 known miRNAs and 270 predicted miRNAs. There were 118 miRNAs expressed at significantly different levels between MCF-7C and MCF-7 cells (P<0.05); among them, 67 miRNAs were upregulated (P<0.05) and 51 miRNA were downregulated (P<0.05). There were 42 miRNAs expressed at significantly different levels between MCF-7T and MCF-7 (P<0.05); among them, 23 miRNAs were upregulated (P<0.05) and 19 miRNAs were downregulated (P<0.05). There were 126 miRNAs with significant differences between MCF-7C and MCF-7T (P<0.05); among them, 76 miRNAs were upregulated (P<0.05) and 50 miRNAs were downregulated. On the basis of the results of the present study, we hypothesize that miR-21, miR-146a, miR-148a, miR-34a and miR-27a may serve important roles in mediating TAM resistance in breast cancer, and have potential as therapeutic targets for TAM-resistant breast cancer.

miR-145 overexpression triggers alteration of the whole transcriptome and inhibits breast cancer development.

Cumulative evidence has associated microRNA (miRNA) with cancer development, and among those miRNAs, miR-145 has been identified as an anti-oncomiRNA. However, the comprehensive mechanisms of action of miR-145 in breast cancer development have not yet been fully elucidated. Herein, we performed next-generation sequencing to detect the expression profiles of the transcriptome and conducted cellular function experiments after miR-145 overexpression. The results verified the inhibitory effects of miR-145 on breast cancer cell proliferation, colony formation, migration and invasion. Sequencing data revealed that miR-145 triggered the alteration of the whole transcriptome and further led to regulation of the competing endogenous RNA (ceRNA) network. Our study also identified a list of 49 target mRNAs of miR-145 and specific non-coding RNAs, which could be utilized as potential breast cancer biomarkers. This study might serve as a significant platform for further research on miR-145 along with the ceRNA network in breast cancer.

Differential Expression Profiles of the Transcriptome in Breast Cancer Cell Lines Revealed by Next Generation Sequencing.

BACKGROUND/AIMS: As MCF-7 and MDA-MB-231 cells are the typical cell lines of two clinical breast tumour subtypes, the aim of the present study was to elucidate the transcriptome differences between MCF-7 and MDA-MB-231 breast cancer cell lines. METHODS: The mRNA, miRNA (MicroRNA) and lncRNA (Long non-coding RNA) expression profiles were examined using NGS (next generation sequencing) instrument Illumina HiSeq-2500. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to identify the biological functions of differentially expressed coding RNAs. Subsequently, we constructed an mRNA-ncRNA (non-coding RNA) targeting regulatory network. Finally, we performed RT-qPCR (real-time quantitative PCR) to confirm the NGS results. RESULTS: There are sharp distinctions of the coding and non-coding RNA profiles between MCF-7 and MDA-MB-231 cell lines. Among the mRNAs and ncRNAs with the most differential expression, SLPI, SOD2, miR-7, miR-143 and miR-145 were highly expressed in MCF-7 cells, while CD55, KRT17, miR-21, miR-10b, miR-9, NEAT1 and PICSAR were over-expressed in MDA-MB-231 cells. Differentially expressed mRNAs are primarily involved in biological processes of locomotion, biological adhesion, ECM-receptor interaction pathway and focal adhesion. In the targeting regulatory network of differentially expressed RNAs, mRNAs and miRNAs are primarily associated with tumour metastasis, but the functions of lncRNAs remain uncharacterized. CONCLUSION: These results provide a basis for future studies of breast cancer metastasis and drug resistance.

Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis.

BACKGROUND/AIMS: Numerous studies have suggested that the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT) is significantly associated with breast cancer. However, these studies have not demonstrated consistent results. METHODS: To obtain more accurate results for this possible association, we performed a meta-analysis-based study using the relevant data. A total of 14 articles were included in this meta-analysis. RESULTS: Our study showed that the frequency of MGMT promoter methylation was significantly higher in patients with breast cancer than non-breast cancer subjects with an Odds Ratio (OR) of 4.47, a 95% Confidence Interval (CI) ranging between 1.95 - 10.25 and a P value of 0.0004. Moreover, MGMT methylation was significantly associated with the negative expression of the MGMT protein (OR = 4.65, 95%CI = 2.66 - 8.12, P < 0.00001), Oestrogen Receptor (ER)-negative tumours (OR = 1.79, 95%CI = 1.09 - 2.93, P = 0.02), postmenopausal status (OR =1.84, 95%CI = 1.18 - 2.87, P = 0.007) and histological grade III tumours (OR = 2.49, 95%CI = 1.53 - 4.07, P = 0.0003) in breast cancer patients. However, breast cancer was not significantly correlated with lymph node metastasis (OR = 1.19, 95%CI = 0.83 - 1.70, P = 0.35), Progesterone Receptor (PR) status (OR = 1.08, 95%CI = 0.58 - 2.00, P = 0.81), Human epidermal growth factor receptor - 2（HER-2/neu）status (OR = 1.01, 95%CI = 0.65 - 1.57, P = 0.97), P53 mutation (OR = 1.30, 95%CI = 0.76 - 2.21, P = 0.34) and age > 50 (OR = 1.07, 95%CI = 0.46 - 2.51, P = 0.88). CONCLUSIONS: Our study suggests that MGMT promoter methylation may be an early biomarker for the diagnosis of breast cancer.

Clinicopathological significance of forkhead box protein A1 in breast cancer: A meta-analysis.

The aim of the present study was to investigate the associations between the expression of forkhead box protein A1 (FOXA1) and differential clinicopathological characteristics in breast cancer using a meta-analysis method. Eligible studies that investigated the correlation between FOXA1 expression and the clinical characteristics of breast cancer were collected through searching numerous databases, including PubMed, EMBASE, the Chinese National Knowledge Infrastructure and the VIP database. In total, eight studies were included in the meta-analysis. Following a systematic analysis, the expression of FOXA1 was found to be significantly associated with the estrogen receptor α status, the progesterone receptor status, lymph node metastasis and the histological grade in breast cancer. However, no statistically significant association was observed between FOXA1 expression and the human epidermal growth factor receptor-2 status in breast cancer patients.

Quantitative assessment of the association between APC promoter methylation and breast cancer.

Adenomatous polyposis coli (APC) is an important tumor suppressor gene in breast cancer. However, there were inconsistent conclusions in the association between APC promoter methylation and breast cancer. Hence, we conducted a meta-analysis to quantitatively assess the clinicopathological significance and diagnosis role of APC methylation in breast cancer. In total, 3172 samples from 29 studies were performed in this study. The odds ratio (OR) of APC methylation was 5.92 (95% CI = 3.16-11.07) in breast cancer cases compared to controls,. The APC promoter methylation was associated with cancer stage (OR = 0.47, 95% CI = 0.28-0.80, P = 0.006), lymph node metastases (OR = 0.55, 95% CI = 0.36-0.84, P = 0.005) and ER status (OR = 1.34, 95% CI = 1.03-1.73, P = 0.003) in breast cancer. Furthermore, the sensitivity and specificity for all included studies were 0.444 (95% CI: 0.321-0.575, P < 0.0001) and 0.976 (95% CI: 0.916-0.993, P < 0.0001), respectively. These results suggested that APC promoter methylation was associated with breast cancer risk, and it could be a valuable biomarker for diagnosis, treatment and prognosis of breast cancer.

SATB1 is Correlated with Progression and Metastasis of Breast Cancers: A Meta-Analysis.

BACKGROUND/AIMS: Several researches have evaluated the significance of SATB1 (Special AT-rich sequence binding protein 1) expression in breast cancers (BCs), but the results have been disputed, especially in the aspects of clinicopathological features and prognosis. Therefore, our study aimed to use a meta-analysis to summarize the clinical and prognostic relevance of SATB1 gene expression in BCs. METHODS: A literature search of PubMed, EMBASE, Cochrane library, Chinese Wanfang and CNKI was performed to identify eligible studies. Ten studies total, comprising 5,185 patients (1,699 SATB1-positive and 3,486 SATB1-negative), were enrolled in our study, which was performed using Revman5.3 Software and Stata11.0 Software. RESULTS: This meta-analysis showed that the expression of SATB1 was significantly higher in breast cancer than in normal tissues (OR = 12.28; 95%CI = 6.01-25.09), and was statistically related to several clinicopathological parameters, including lymph node metastasis (OR = 1.55, 95%CI = 1.01-2.39) and Tumor Node Metastasis(TNM) stage (OR = 0.35, 95%CI = 0.22-0.56). However, the level of SATB1 was not statistically associated with the age (OR = 1.13, 95%CI = 0.87-1.46), tumour size (OR = 0.72, 95%CI = 0.44-1.19), estrogen receptor (OR = 0.78, 95%CI = 0.55-1.09), progesterone receptor (OR = 0.64, 95%CI = 0.32-1.29), HER2 status (OR=1.98, 95%CI = 0.74-5.30), and histological type (OR = 0.49, 95%CI = 0.22-1.11). CONCLUSION: High expression of SATB1 was significantly correlated with tumourigenesis and metastasis of BCs, indicating poor prognosis for patients. SATB1 could serve as a potential marker for detection and prognosis evaluation of breast cancers.

Association of BRCA1 promoter methylation with sporadic breast cancers: Evidence from 40 studies.

Breast cancer susceptibility gene 1 (BRCA1) located at chromosome 17q12-21 is a classic tumor suppressor gene, and has been considered as a significant role in hereditary breast cancers. Moreover, numerous studies demonstrated the methylation status of CpG islands in the promoter regions of BRCA1 gene was aberrant in patients with sporadic breast tumors compared with healthy females or patients with benign diseases. However, these conclusions were not always consistent. Hence, a meta-analysis was performed to get a more precise estimate for these associations. Crude odds ratio with 95% confidence interval were used to assess the association of BRCA1 promoter methylation and the risk or clinicopathologic characteristics of breast cancers under fixed or random effect model. A total of 40 studies were eligible for this present study. We observed the frequency of BRCA1 promoter methylation was statistically significant higher in breast cancers than non-cancer controls. Furthermore, BRCA1 methylation was statistically associated with lymph node metastasis, histological grade 3, ER(-), PR(-), triple-negative phenotype, and decreased or lack levels of BRCA1 protein expression. In conclusion, this study indicated that BRCA1 promoter methylation appeared to be a useful predictive or prognostic biomarker for breast cancers in clinical assessment.

Aberrant GSTP1 promoter methylation is associated with increased risk and advanced stage of breast cancer: a meta-analysis of 19 case-control studies.

BACKGROUND: Glutathione S-transferase P1 (GSTP1) has been reported to function as a tumor suppressor gene in various types of human cancers. Aberrant methylation of tumor-related genes at the promoter regions can inactivate genes, which is important in the carcinogenesis of breast cancer. However, the role of GSTP1 promoter methylation in the occurrence of breast cancer and its relationship with tumor stage and histological grade has not been fully elucidated. Thus, we carried out a meta-analysis to yield a more accurate association. METHODS: A systematically literature search was made on PubMed, EMBASE and Web of Science databases for eligible studies. The odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated by RevMan 5.2 software. Subgroup and sensitivity analyses were conducted to explore the source of heterogeneity. RESULTS: Eventually, 17 articles involving 19 case-control studies were included in the present meta-analysis. Overall, the pooled results indicated that aberrant GSTP1 promoter methylation was significantly associated with the risk of breast cancer (OR = 7.85, 95 % CI = 5.12-12.01; Caucasians OR = 7.23, 95 % CI = 3.76-13.90 and Asians OR = 11.71, 95 % CI = 5.69-24.07). Furthermore, our results revealed that GSTP1 promoter methylation was more often observed in late-stage breast cancer patients compared with early-stage ones (OR = 1.84, 95 % CI = 1.32-2.58). However, no significant association was identified between GSTP1 promoter methylation and histological grade (OR = 0.74, 95 % CI = 0.43-1.26). CONCLUSIONS: The results indicated that GSTP1 promoter methylation probably plays an important role in breast carcinogenesis, which could serve as an effective biomarker for the diagnosis and monitor of breast cancer.

Association of three SNPs in TOX3 and breast cancer risk: Evidence from 97275 cases and 128686 controls.

The associations of SNPs in TOX3 gene with breast cancer risk were investigated by some Genome-wide association studies and epidemiological studies, but the study results were contradictory. To derive a more precise estimate of the associations, we conducted a meta-analysis. ORs with 95% CI were used to assess the strength of association between TOX3 polymorphisms and breast cancer risk in fixed or random effect model. A total of 37 publications with 97275 cases and 128686 controls were identified. We observed that the rs3803662 C > T, rs12443621 A > G and rs8051542 C > T were all correlated with increased risk of breast cancer. In the stratified analyses by ethnicity, significantly elevated risk was detected for all genetic models of the three SNPs in Caucasians. In Asian populations, there were significant associations of rs3803662 and rs8051542 with breast cancer risk. Whereas there was no evidence for statistical significant association between the three SNPs and breast cancer risk in Africans. Additionally, we observed different associations of rs3803662 with breast cancer risk based on different ER subtype and BRCA1/BRCA2 mutation carriers. In conclusion, the meta-analysis suggested that three SNPs in TOX3 were significantly associated with breast cancer risk in different populations.

Association of the pri-miR-124-1 rs531564 polymorphism with cancer risk: A meta-analysis.

Recently, several studies regarding the association between the pri-miR-124-1 rs531564 polymorphism and cancer susceptibility were explored. Owing to inconsistent results of these studies, a meta-analysis was conducted to determine the association of this polymorphism with cancer risk. Relevant studies were identified by a systematic search of PubMed, EMBASE, Web of Science and CNKI on-line databases. Odds ratios (ORs) and 95% confidence intervals (CIs) from eligible studies were pooled, and heterogeneity and publication bias were also evaluated. A total of five studies with 2,253 cases and 2,510 controls were included in the meta-analysis. Overall, the results showed that the pri-miR-124-1 rs531564 polymorphism was significantly associated with a reduced cancer risk (G vs. C: OR, 0.86; 95% CI, 0.77-0.96; GG vs. CC: OR, 0.52; 95% CI, 0.34-0.79; GG vs. CG/CC: OR, 0.54; 95% CI, 0.36-0.81). Furthermore, in the subgroup analysis by cancer sites, a statistical association was identified between the rs531564 polymorphism and a decreased esophageal squamous cell carcinoma (ESCC) risk (G vs. C: OR, 0.87; 95% CI, 0.77-0.98; GG vs. CC: OR, 0.54; 95% CI, 0.34-0.84). These findings suggested that the genetic variant of rs531564 may have a potential value in decreasing cancer risk, particularly in ESCC patients.