MCM2 is involved in subtyping and tamoxifen resistance of ERα-positive breast cancer by acting as the downstream factor of ERα.

Tamoxifen (TAM) resistance is finally developed in over 40% of patients with estrogen receptor α-positive breast cancer (ERα+ -BC), documenting that discovering new molecular subtype is needed to confer perception to the heterogeneity of ERα+ -BC. We obtained representative gene sets subtyping ERα+ -BC using gene set variation analysis (GSVA), non-negative matrix factorization (NMF), and COX regression methods on the basis of METABRIC, TCGA, and GEO databases. Furthermore, the risk score of ERα+ -BC subtyping was established using least absolute shrinkage and selection operator (LASSO) regression on the basis of genes in the representative gene sets, thereby generating the two subtypes of ERα+ -BC. We further found that minichromosome maintenance complex component 2 (MCM2) functioned as the hub gene subtyping ERα+ -BC using GO, KEGG, and MCODE. MCM2 expression was capable for specifically predicting 1-year overall survival (OS) of ERα+ -BC and correlated with T stage, AJCC stage, and tamoxifen (TAM) sensitivity of ERα+ -BC. The downregulation of MCM2 expression inhibited proliferation, migration, and invasion of TAM-resistant cells and promoted G0/G1 arrest. Altogether, tamoxifen resistance entails that MCM2 is a hub gene subtyping ERα+ -BC, providing a novel dimension for discovering a potential target of TAM-resistant BC.

MiR-204-5p-targeted AP1S2 is necessary for papillary thyroid carcinoma.

MiR-204-5p, as a tumour suppressor, has been found in several cancers. However, whether miR-204-5p is involved in papillary thyroid carcinoma (PTC) has not yet been investigated. In this study, we identified miR-204-5p as a down-regulated miRNA in PTC tissues, unveiling that the levels of miR-204-5p in serum of patients with PTC were linked to PTC risk, and that the expression in patients concomitant with both PTC and benign lesions was much lower than that in patients only with PTC. Furthermore, we documented that miR-204-5p inhibited proliferation, migration, invasion, and cell cycle progression and triggered apoptosis of PTC cells via cell biology experiments. Finally, we identified that AP1S2 was a target of miR-204-5p using RNA-seq, iTRAQ, and bioinformatics prediction. Overall, miR-204-5p functions as a suppressor for PTC pathogenesis via the miR-204-5p/AP1S2 axis.

Nexus between genome-wide copy number variations and autism spectrum disorder in Northeast Han Chinese population.

BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder, with an increasing prevalence worldwide. Copy number variation (CNV), as one of genetic factors, is involved in ASD etiology. However, there exist substantial differences in terms of location and frequency of some CNVs in the general Asian population. Whole-genome studies of CNVs in Northeast Han Chinese samples are still lacking, necessitating our ongoing work to investigate the characteristics of CNVs in a Northeast Han Chinese population with clinically diagnosed ASD. METHODS: We performed a genome-wide CNVs screening in Northeast Han Chinese individuals with ASD using array-based comparative genomic hybridization. RESULTS: We found that 22 kinds of CNVs (6 deletions and 16 duplications) were potentially pathogenic. These CNVs were distributed in chromosome 1p36.33, 1p36.31, 1q42.13, 2p23.1-p22.3, 5p15.33, 5p15.33-p15.2, 7p22.3, 7p22.3-p22.2, 7q22.1-q22.2, 10q23.2-q23.31, 10q26.2-q26.3, 11p15.5, 11q25, 12p12.1-p11.23, 14q11.2, 15q13.3, 16p13.3, 16q21, 22q13.31-q13.33, and Xq12-q13.1. Additionally, we found 20 potential pathogenic genes of ASD in our population, including eight protein coding genes (six duplications [DRD4, HRAS, OPHN1, SHANK3, SLC6A3, and TSC2] and two deletions [CHRNA7 and PTEN]) and 12 microRNAs-coding genes (ten duplications [MIR202, MIR210, MIR3178, MIR339, MIR4516, MIR4717, MIR483, MIR675, MIR6821, and MIR940] and two deletions [MIR107 and MIR558]). CONCLUSION: We identified CNVs and genes implicated in ASD risks, conferring perception to further reveal ASD etiology.

Transcription factor AP-2 gamma/Krüppel-like factor 10 axis is involved in miR-3656-related dysfunction of endothelial cells in hypertension.

BACKGROUND: Dysfunction of endothelial cells links to microvascular rarefaction, reflecting the pathogenesis of hypertension. Our previous studies found that miR-3656 reduces nitric oxide generation and von Willebrand factor (vWF) cleavage, thereby retarding blood flow and potentially increasing blood pressure. In this paper, we investigated mechanism of transcription regulation contributing to miR-3656-damaged endothelial cells in hypertension. METHODS: The effects of miR-3656 on function of endothelial cells were analyzed on the basis of proliferation, migration, tube formation, and apoptosis. The mRNA level and protein level of genes were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Dual-luciferase reporter assay was performed to confirm the binding between miR-3656 and 3' untranslated region (UTR) of transcription factor AP-2 gamma ( TFAP2C ). The binding between TFAP2C and the promoter region of Krüppel-like factor 10 ( KLF10 ) was confirmed by chromatin immunoprecipitation-qPCR assay. RESULTS: miR-3656 impaired the cell proliferation, migration, tube formation, and apoptosis of endothelial cells. miR-3656 inhibited the expression of TFAP2C by directly targeting 3'UTR of TFAP2C ; moreover, miR-3656-induced injury of endothelial cells was rescued by TFAP2C overexpression. Furthermore, downregulated TFAP2C decreased KLF10 expression by binding to KLF10 promoter region, and upregulated KLF10 reversed the effects of silencing TFAP2C on endothelial cells. These inhibitory processes led to interference of miR-3656 to KLF10-promoted function of endothelial cells. CONCLUSION: TFAP2C/KLF10 axis is involved in miR-3656-related dysfunction of endothelial cells in hypertension. The 3'UTR of TFAP2C and KLF10 promoter region are the hubs of the TFAP2C/KLF10 axis.

Meta-analysis of the association between Apolipoprotein E polymorphism and risks of myocardial infarction.

BACKGROUND: Myocardial infarction (MI) remains the leading cause of death and disability among cardiovascular diseases worldwide. Studies show that elevated low-density lipid protein cholesterol (LDL-C) levels confer the highest absolute risk of MI, and Apolipoprotein E (ApoE) is implicated in regulating levels of triglycerides (TGs), cholesterol, and LDL-C. Our study aimed to evaluate the association between APOE polymorphism and MI, and to provide evidence for the etiology of MI. METHODS: Case-control studies on the association between APOE polymorphisms and the risk of myocardial infarction were included by searching PubMed, Web of Science, and CNKI, and this meta-analysis was written in accordance with PRISMA guideline statement. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either random-effects or fixed-effects models by R software. RESULTS: A total of 33 eligible articles involving 13,706 cases and 14,817 controls were finally selected. The pooled analysis based on the total eligible articles showed that the risk of MI was associated with ApoE epsilon 2 and epsilon 4 alleles. The results showed that patients with MI had a low frequency of the ε2 allele (OR 0.74, 95% CI 0.64-0.86) and a high frequency of the ε4 allele (OR 1.24, 95% CI 1.09-1.42). CONCLUSIONS: APOE ε2-involved genotypes may be protective factors for MI; in contrast, ε4-involved genotypes (ε4/ε3 vs. ε3/ε3, and ε4/ε4 vs. ε3/ε3) may be risk factors for MI.

Epidemiological status quo of hypertension in elderly population in Changchun, China: a cross-sectional study.

OBJECTIVES: To investigate the epidemiological status quo of hypertension in elderly population in Changchun, China, and provide a reference for the prevention and control strategies of hypertension of elderly population in this region. DESIGN: A cross-sectional study, as a part of a comprehensive project in Northeast China, was designed to perform in 10 districts in Changchun. PARTICIPANTS AND SETTING: A total of 6846 participants who were ≥60 years old were selected using a random sampling method. MAIN OUTCOME MEASURES: The epidemiological status quo of hypertension. RESULTS: The prevalence of hypertension in Changchun was 52.6%. Among participants with hypertension enrolled in this study, 87.6% of the participants had been diagnosed with hypertension before the study, 69.1% was taking antihypertensive medications and 66.9% had effective blood pressure control. Obesity, widower/widow, history of diseases and family history of hypertension were risk factors of hypertension (all p<0.05). Participants with obesity, a personal history of heart coronary disease, or a family history of hypertension were susceptible to realising risks of hypertension (all p<0.05). However, participants with diabetes, hyperlipidaemia, or a family history of hypertension were difficult to control blood pressure within the normal range (all p<0.05). In addition, 92.6% participants taking antihypertensive medications used a single medication, and calcium channel blockers was the most commonly used antihypertensive medications in monotherapy. CONCLUSION: The rates of awareness, treatment and control of hypertension are greater in Changchun than those in China, indicating that the prevention and control of hypertension in Changchun are effective. However, the prevalence of hypertension in the elderly population in China is lower than that in Changchun, also rendering Changchun a substantial challenge for the supervision of hypertension.

Circulating miR-3656 induces human umbilical vein endothelial cell injury by targeting eNOS and ADAMTS13: a novel biomarker for hypertension.

BACKGROUND: Hypertension, as one of the most common chronic diseases, is a major public health issue. Previous studies have shown that there are miRNAs differentially expressed in hypertensive patients. In addition, hypertension is closely related to endothelial dysfunction, and miRNAs have been identified as important molecular mediators for endothelial function. Therefore, it is necessary to identify specific miRNAs related to hypertension and explore their molecular mechanism in the progression of hypertension. METHODS: We investigated the association of circulating levels of miR-3656 with hypertension. Furthermore, in-vitro studies were performed to investigate its possible mechanisms for hypertension in that the direct target genes of miR-3656 were confirmed using dual-luciferase reporter assay; moreover, the effects of miR-3656 on proliferation, migration, apoptosis, and microvascular rarefaction of HUVECs were investigated using MTS kit, wound-healing assay, FITC Annexin V apoptosis detection kit, and tube formation assay, correspondingly. RESULTS: Circulating miR-3656 was upregulated in patients with hypertension. MiR-3656 suppressed the proliferation, migration, and angiogenesis of HUVECs, but promoted the apoptosis of HUVECs. In addition, eNOS and ADAMTS13 were direct target genes of miR-3656, and overexpression of eNOS and ADAMTS13 abolished the effect of miR-3656 on HUVECs. CONCLUSION: MiR-3656 is a potential biomarker for hypertension. MiR-3656 is involved in endothelial cellular injury implicated in hypertension by targeting eNOS and ADAMTS13.

OLFML2A is necessary for anti-triple negative breast cancer effect of selective activator protein-1 inhibitor T-5224.

Previous studies have shown that expression of activator protein-1 (AP-1) family is significantly elevated in triple-negative breast cancer (TNBC), compared with that in other breast cancer subtypes. Here we investigated the anti-tumor effect and mechanism of T-5224, an inhibitor of c-Fos/AP-1, on TNBC. We identified that T-5224 inhibited the proliferation, migration, and invasion of TNBC cells and resulted in an increase in apoptosis. Furthermore, we found that OLFML2A is a key regulatory protein acting downstream of AP-1 and is involved in T-5224-targeted AP-1 action. Multiple clinical databases online have identified that high OLFML2A level is associated with poor prognosis in TNBC patients. In summary, our experimental and bioinformatic studies indicated that OLFML2A is necessary for AP-1-overexpressing TNBC. These findings demonstrate that AP-1-overexpressing TNBC dependent on OLFML2A, and targeting both AP-1 and OLFML2A through T-5224 may be a synergistic therapeutic strategy for this clinically challenging subset of breast cancer.

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more commonly associated with young patients, featuring high histological grade, visceral metastasis, and distant recurrence. Follistatin (FST) is a secreted extracellular regulatory protein that antagonizes TGF-ß superfamily such as activin and TGF-ß related superfamily such as bone morphogenetic protein (BMP). The implication of FST in the proliferation, angiogenesis, and metastasis of solid tumors documents good or poor outcome of patients with BC. However, the role of FST in TNBC remains unclear. METHODS: Data of 935 patients with breast cancer (BC) were extracted from TCGA. Case-control study, Kaplan-Meier, uni-multivariate COX, and ROC curve were utilized to investigate the relationship between FST expression and the clinical characteristics and prognosis of BC. Functional studies were used to analyze the effect of FST expression on proliferation, apoptosis, migration, and invasion of TNBC cell lines. Bioinformatic methods such as volcanoplot, GO annd KEGG enrichment, and protein-protein interactions (PPI) analyses were conducted to further confirm the different roles of FST in the apoptotic pathways among mesenchymal and mesenchymal stem-like cells of TNBC. RESULTS: Data from TCGA showed that low FST expression correlated with poor prognosis (for univariate analysis, HR = 0.47, 95% CI: 0.27-0.82, p = 0.008; for multivariate analysis, HR = 0.40, 95% CI: 0.21-0.75, p = 0.004). Low FST expression provided high predicted value of poor prognosis in TNBC amongst BCs. FST knockdown promoted the proliferation, migration and invasion of BT549 and HS578T cell lines. FST inhibited the apoptosis of mesenchymal cells by targeting BMP7. CONCLUSIONS: Low FST expression is associated with poor prognosis of patients with TNBC. FST expressions exhibit the anisotropic roles of apoptosis between mesenchymal and mesenchymal stem-like cells but promote the proliferation, migration, invasion in both of two subtypes of TNBC in vitro. FST may be a subtype-heterogeneous biomarker for monitoring the progress of TNBC.

ε2 allele and ε2-involved genotypes (ε2/ε2, ε2/ε3, and ε2/ε4) may confer the association of APOE genetic polymorphism with risks of nephropathy in type 2 diabetes: a meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) contributes to end-stage renal failure. Microvascular injury resulted from reactive oxygen species is implicated in the pathogenesis of DN. Genetic polymorphism of Apolipoprotein E (APOE) influences the antioxidative properties of the protein. The relationship of APOE polymorphism with the risks of nephropathy in type 2 diabetes (T2DN) remains elusive. METHODS: An up-to-date meta-analysis was conducted on the basis of studies selected from PubMed, WanFang database, Embase, Vip database, Web of Science, Scopus, and CNKI database. RESULTS: A total of 33 studies conferring 3266 cases and 3259 controls were selected on the basis of criteria of inclusion and exclusion in this meta-analysis. For APOE alleles, the pooled odds ratio (OR) of ε2 vs. ε3 was 1.89 (95% confidence intervals [95% CI]: 1.49-2.38, P < 0.0001). With regard to APOE genotypes, ε2/ε2, ε2/ε3, and ε2/ε4 increased the risk of T2DN (ε2/ε2 vs. ε3/ε3: OR = 2.32, 95% CI: 1.52-3.56, P = 0.0001; ε2/ε3 vs. ε3/ε3: OR = 1.97, 95% CI: 1.50-2.59, P<0.0001; ε2/ε4 vs. ε3/ε3: OR = 1.69, 95% CI: 1.18-2.44, P = 0.0046). CONCLUSIONS: This meta-analysis found that the APOE ε2 allele and the ε2-involved genotypes (ε2/ε2, ε2/ε3, and ε2/ε4) are the risk factors of T2DN.

Prevalence of autism spectrum disorder in Asia: A systematic review and meta-analysis.

There has been an increased prevalence of the diagnosis of Autism Spectrum Disorder (ASD) globally during the last decade. An updated and overall estimate of ASD prevalence in Asia would assist health professionals to develop relevant public health strategies. We performed a systematic review by searching English databases (Medline, Embase, Web of Science, and Cochran Library) from inception date to August 6, 2018. Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Publication bias was evaluated using Egger's test. A total of 2,195,497 subjects in Asia from 12 eligible studies were included in this meta-analysis. The pooled estimate of ASD prevalence among the included subjects was 0.36% (95% CI: 0.16-0.79%). The pooled ASD prevalence in males (0.45%, 95% CI: 0.19-1.04%) was higher than that in females (0.18%, 95% CI: 0.079-0.49%). ASD prevalence in East Asia, South Asia, and West Asia was 0.51% (95% CI: 0.06-4.22%), 0.31% (95% CI: 0.14-0.65%), and 0.35% (95% CI: 0.07-1.80%) respectively. The prevalence of ASD is increasing in Asia. Universal and standardized diagnostic processes for ASD should be adopted for the prevention and control programs of ASD in future.

Social-biological influences on sleep duration among adult residents of Northeastern China.

BACKGROUND: Cold climates traditionally have conferred long sleep duration in the residents in northeast China; however, modern lifestyle reduces sleep duration. In this study, we investigated social-biological factors influencing sleep duration in the adult residents in northeast China. METHODS: This study was performed using data from the Investigation of Chronic Disease Morbidity Rate and Risk Factors of Adults in Jilin Province, China. Associations between sleep duration and indices of demographic characteristics, health-related behaviors, and disease history in adult residents were analyzed using univariate analysis and multivariate logistic regression analysis. RESULTS: The mean sleep duration was 7.24 h. Of the 21,435 participants, approximately 53.4% had short sleep duration (sleep duration per day < 7 h), and 10.5% had long sleep duration (sleep duration per day > 9 h). There were associations between short sleep duration and indices, including age, place of residence, marital status, educational level, alcohol drinking, dietary, obesity, and history of coronary heart disease (CHD) or myocardial infarction (MI). There existed associations of long sleep duration with indices, such as age, place of residence, occupation, educational level, average monthly earnings, and physical exercise. CONCLUSION: Short sleep duration is common among residents in northeast China. Age, place of residence, and educational level are implicated in both short sleep duration and long sleep duration. Short sleep duration inclines to link with the indices (marital status, alcohol drinking, dietary, obesity, and history of CHD or MI). However, long sleep duration is relevant to the indices (occupation, average monthly earnings, and physical exercise).

SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age.

Autism spectrum disorder (ASD) is a serious lifelong neurodevelopmental disorder. ASD is diagnosed for children at the age of two. ASD diagnosis, as early as possible, lays the foundation for treatment and much better prognosis. Notably, gene-based test is an inherent method to recognize the potential infants with ASD before the age of two. To investigate whether SHANK family contributes to ASD prediction, on the basis of our previous studies of SHANK2 and SHANK3, we further investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP-SNP interactions among SHANK family. We enrolled 470 subjects (229 cases and 241 healthy controls) who were northeast Chinese Han. Four tag SNPs (rs73042561, rs3745521, rs4801846, and rs12461427) of SHANK1 were selected and genotyped. We used the SNPStats online analysis program to assess the associations between the four SNPs and ASD risk. The SNP-SNP interactions among SHANK family were analyzed using multifactor dimensionality reduction method. We found that the four SHANK1 SNPs were not associated with ASD risk in northeast Chinese Han population. There existed a strong synergistic interaction between rs11236697 [SHANK2] and rs74336682 [SHANK2], and moderate synergistic interactions (rs74336682 [SHANK2]-rs73042561 [SHANK1], rs11236697 [SHANK2]-rs77716438 [SHANK2], and rs11236697 [SHANK2]-rs75357229 [SHANK2]). These SHANK1 variants may not affect the susceptibility to ASD in Chinese Han population. SNP-SNP interactions in SHANK family may confer ASD risk. Autism Res 2019, 12: 375-383 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: ASD is a serious lifelong neurodevelopmental disorder with strong genetic components. We investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP-SNP interactions among SHANK family. Our results indicated that there exists no association between SHANK1 SNPs and ASD, and SNP-SNP interactions in SHANK family may confer ASD risk in the Northeast Han Chinese population. Future studies are needed to test more SHANK family SNPs in a large sample to demonstrate the associations.

Association between ATM rs1801516 polymorphism and cancer susceptibility: a meta-analysis involving 12,879 cases and 18,054 controls.

BACKGROUND: Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis. METHODS: Studies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk. RESULTS: A total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons (AA vs GG + GA: OR = 0.91, 95% CI, 0.78-1.07; AA+GA vs GG: OR = 1.00, 95% CI, 0.90-1.11; AA vs GG: OR = 0.89, 95% CI, 0.75-1.06; GA vs GG: OR = 1.01, 95% CI, 0.91-1.13; GG + AA vs GA: OR = 1.00, 95% CI, 0.88-1.10). However, after subgroup analyses by region-specified population, significant associations were found in European (AA vs GG + GA: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017; AA vs GG: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017), South American (AA+GA vs GG: OR = 2.15, 95% CI, 1.37-3.38, P = 0.001; GA vs GG: OR = 2.19, 95% CI, 1.38-3.47, P = 0.001; GG + AA vs GA: OR = 0.46, 95% CI, 0.29-0.72, P = 0.001), and Asian (AA vs GG + GA: OR = 7.45, 95% CI, 1.31-42.46, P = 0.024; AA vs GG: OR = 7.40, 95% CI, 1.30-42.19, P = 0.024). Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer (AA vs GG: OR = 0.76, 95% CI, 0.59-0.98, P = 0.035), and the homozygote AA was associated with decreased cancer risk in subjects with family history (AA vs GG: OR = 0.68, 95% CI, 0.47-0.98, P = 0.039). CONCLUSIONS: ATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, this polymorphism is especially associated with breast cancer risk; in addition, it is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history.

PREVALENCE AND RISK FACTORS OF IMPAIRED FASTING GLUCOSE AMONG ADULTS IN NORTHEAST CHINA: A CROSS-SECTIONAL STUDY.

OBJECTIVE: To investigate the prevalence and risk factors of impaired fasting glucose (IFG) among adults in northeast China. METHODS: A cross-sectional study was conducted in Jilin Province in 2012. Questionnaires were used to collect information about demographic characteristics, lifestyle factors, and health status from 15,540 residents. Fasting blood glucose (FBG) was measured in the morning after at least 12 hours of fasting, and χ2 tests were performed to compare differences between subjects with and without IFG. Logistic regression was carried out to identify factors influencing IFG occurrence. RESULTS: There were significant differences in demographic characteristics (age, sex, education, and marriage status), lifestyle factors (smoking, drinking, physical activity, and average sleep duration), and health status (hyperlipidemia, hypertension, and BMI category) between subjects with IFG and without IFG ( P<.05). IFG risk was significantly associated with sex, age, education (senior high school and college), marriage status (single), drinking, hyperlipidemia, hypertension, and BMI category (all P<.05). CONCLUSION: In adults in northeast China, risk factors of IFG are sex, age, education (senior high school and college), drinking, hyperlipidemia, hypertension, and BMI category; however, the protective factor of IFG is marriage status (single). ABBREVIATIONS: BMI = body mass index; CI = confidence interval; FBG = fasting blood glucose; IFG = impaired fasting glucose; OR = odds ratio; T2DM = type 2 diabetes.

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression.

Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFα can facilitate tumor progression and metastasis. However, the mechanistic aspects of inflammation mediated TNBC progression remain unclear. Using ChIP-seq, we demonstrate that the cistrome for the AP-1 transcription factor c-Jun is comprised of 13,800 binding regions in TNFα-stimulated TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFα-regulated transcriptome. Interestingly, high expression level of the c-Jun-regulated pro-invasion gene program is associated with poor clinical outcome in TNBCs. We further demonstrate that c-Jun drives TNFα-mediated increase of malignant characteristics of TNBC cells by transcriptional regulation of Ninj1. As exemplified by the CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-κB might be a pioneer factor required for the regulation of TNFα-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.

Association of NCOA3 polymorphisms with Dyslipidemia in the Chinese Han population.

BACKGROUND: Nuclear receptor coactivator-3 (NCOA3) is involved in various physiological processes. Emerging evidence from previous studies using animal models suggests that the NCOA3 gene (NCOA3) plays a critical role in lipid metabolism as well as adipogenesis and obesity. The present study aims to investigate the association between NCOA3 SNPs and dyslipidemia in the Chinese Han population. METHODS: Five hundred and twenty-nine (529) Chinese Han subjects were recruited. Four tag SNPs (rs2425955G > T, rs6066394T > C, rs10485463C > G, and rs6094753G > A) in NCOA3, selected from the HapMap website, were genotyped using MALDI-TOF mass spectrometry. Data analysis was performed using SPSS 16.0, SNPStats and haploview 4.2. RESULTS: Four SNPs (rs2425955, rs6066394, rs10485463, and rs6094753) were associated with triglyceride levels. Except for SNP rs10485463, genotype distributions and allele frequencies of the other three NCOA3 SNPs (rs2425955, rs6066394, and rs6094753) were significantly different between hypertriglyceridemia subjects and normal group. Significant differences were also observed in allele frequencies and genotype distributions of SNP rs10485463 between low-HDL cholesterolemia subjects and normal group. Carriers of rs2425955 T allele had a lower risk of hypertriglyceridemia compared to GG genotype. Similar results were observed from rs6094753. Subjects with rs6066394 CT genotype had a lower risk of hypertriglyceridemia than those with the TT genotype; however, CC and TT genotypes showed no significant difference in the risk of hypertriglyceridemia. Similar results were found in the association between rs6066394 and hypercholesterolemia. The variant alleles of rs2425955, rs6066394 and rs6094753 were associated with a lower risk of hypertriglyceridemia compared with the wild-type alleles. The G allele of rs10485463 was associated with an increased risk of low-HDL cholesterolemia. In the log-additive model the association between rs2425955 and hypertriglyceridemia remained significant after Bonferroni correction, and genotypes with variant alleles were associated with a lower risk of hypertriglyceridemia. CONCLUSIONS: In summary, this study demonstrated that variation in NCOA3 might influence the risk of dyslipidemia and serum lipid levels in Chinese Han population.

Association of NCOA2 gene polymorphisms with obesity and dyslipidemia in the Chinese Han population.

BACKGROUND: Nuclear receptor coactivator 2 (NCOA2) gene plays an important role in adipogenesis and lipid metabolism. NCOA2 gene null mice exhibited less fat accumulation and lower serum lipid levels, and were protected against obesity. Few studies are known to have analyzed the association of NCOA2 gene single nucleotide polymorphisms with obesity and serum lipid profile. Our study aimed to evaluate the association of NCOA2 gene polymorphisms with the risk of obesity and dyslipidemia in the Chinese Han population. METHODS: Two NCOA2 gene polymorphisms (rs41391448 and rs10504473) were selected and genotyped in a Chinese Han cohort with 529 participants. The effect of different genotypes on BMI and serum lipid levels (TG, TC, LDL-C and HDL-C) was performed by the analysis of covariance. Association of NCOA2 polymorphisms with obesity and dyslipidemia was assessed by odds ratios (OR) and 95% confidence intervals (CI) under the unconditional logistic regression analysis. RESULTS: Significant association was observed between rs10504473 polymorphism and obesity under the recessive model (OR = 1.88, 95% CI 1.02-3.45, P = 0.047; adjusted OR = 1.87, 95% CI 1.02-3.44, P = 0.048). However, no association remained significant after Bonferroni correction. CONCLUSION: Our study suggests a possible association between NCOA2 rs10504473 polymorphism and obesity, and this SNP may influence the susceptibility of obesity in the Chinese Han population.

AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.

The molecular determinants of malignant cell behaviour in triple-negative breast cancer (TNBC) are poorly understood. Recent studies have shown that regulators of epithelial-mesenchymal transition (EMT) are potential therapeutic targets for TNBC. In this study, we demonstrate that the inflammatory cytokine TNFα induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1. We further investigated in detail AP-1 regulation of ZEB2 expression. We show that two ZEB2 transcripts derived from distinct promoters are both expressed in breast cancer cell lines and breast tumor samples. Using the chromosome conformation capture assay, we demonstrate that AP-1, when activated by TNFα, binds to a site in promoter 1b of the ZEB2 gene where it regulates the expression of both promoter 1b and 1a, the latter via mediating long range chromatin interactions. Overall, this work provides a plausible mechanism for inflammation-induced metastatic potential in TNBC, involving a novel regulatory mechanism governing ZEB2 isoform expression.