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PDF file - 41KB, Validation of ChIP-seq data by real-time PCR.

PDF file - 105KB, Fra-1 or c-Jun depletion reduces proliferation.

PDF file - 86KB, Examination of knockdown efficiency after siRNA transfection and validation of microarray data by real-time PCR.

PDF file - 198KB, Validation of the PI3K Inhibitor LY294002 repressing Fra-1 and c-Jun expression in MDA-MB-231 and Hs578T TNBC cell lines.

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PDF file - 128KB, Validation of AP-1 mediated downregulation of E-cadherin expression through transcriptional induction of ZEB2 in the Hs578T TNBC cell line.

PDF file - 20KB, Chromosomal positions of Fra-1 and c-Jun co-occupied regions.

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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 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, PP = 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.

ObjectivesTo 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.DesignA cross-sectional study, as a part of a comprehensive project in Northeast China, was designed to perform in 10 districts in Changchun.Participants and settingA total of 6846 participants who were ≥60 years old were selected using a random sampling method.Main outcome measuresThe epidemiological status quo of hypertension.ResultsThe 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 pConclusionThe 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.

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.

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 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).

Background: Autism spectrum disorder (ASD) is a common neurodevelopmental condition, 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 22 kinds of CNVs (six deletions and 16 duplications) were potential 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 genes (ten duplications [MIR202, MIR210, MIR3178, MIR339, MIR4516, MIR4717, MIR483, MIR675, MIR6821, and MIR940] and two deletions [MIR107 and MIR558]).Limitations: The sample size in our study may confer limited statistical power to discover significant findings. De novo or inherited of the CNVs were not be classified because of the lack of data from parents.Conclusions: We identified CNVs and genes implicated in ASD risks, conferring perception to further reveal ASD etiology.

Additional file 2: Table S2. Primer sequences of 36B4 and FST.

Additional file 1: Table S1. Nonconditional logistic analysis for FST and some clinicopathologic characteristics.

Additional file 4: Figure S2. FST expression in siRNA targeted FST model and the role of FST in apoptotic pathways between BT549 and HS578T cells.

Additional file 3: Figure S1. Kaplan–Meier OS analysis of FST expression for patients with pathological stage I-II, distant metastasis free, lymph node free and PR positive BCs in TCGA and KM plotter.

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-β superfamily such as activin and TGF-β 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.

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. Electronic supplementary material The online version of this article (10.1186/s12885-018-4941-1) contains supplementary material, which is available to authorized users.

To investigate the prevalence and risk factors of impaired fasting glucose (IFG) among adults in northeast China.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 χThere 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).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).BMI = body mass index; CI = confidence interval; FBG = fasting blood glucose; IFG = impaired fasting glucose; OR = odds ratio; T2DM = type 2 diabetes.

Highlights • 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. • T-5224, an inhibitor of c-Fos/AP-1 resulted in increase of apoptosis and inhibition of proliferation, migration, and invasion of TNBC cells. • High OLFML2A level is associated with poor prognosis in TNBC patients that were identified from multiple clinical data sets on line. • AP1-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., 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.

Additional file 1: Figure S1. Funnel plot of the association between ApoE gene polymorphism and nephropathy in type 2 diabetes. (A) ε2 allele (B) ε4 allele (C) ε2/ε2 genotype (D) ε2/ε3 genotype (E) ε2/ε4 genotype (F) ε3/ε4 genotype (G)ε4/ε4 genotype. Figure S2. Trial sequential analysis of the association between ApoE gene polymorphism and nephropathy in type 2 diabetes. (A) ε2 allele; (B) ε2/ε2 genotype; (C) ε2/ε3 genotype; (D) ε2/ε4 genotype. Figure S3. Trial sequential analysis of the association between ApoE gene polymorphism and nephropathy in type 2 diabetes. (A) ε4 allele; (B) ε3/ε4 genotype; (C) ε4/ε4 genotype.

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.

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.

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.

Table S1. Matching criteria and genotyping method of the eligible studies included in the meta-analysis. (DOCX 24 kb)

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.

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1–regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell–cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983–94. ©2014 AACR.

Estrogen receptor α (ERα) is initially expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression by regulating the transcription of genes linked to cell proliferation. ERα status is of clinical importance, as ERα-positive breast cancers can be successfully treated by adjuvant therapy with antiestrogens or aromatase inhibitors. Complications arise from the frequent development of drug resistance that might be caused by multiple alterations, including components of ERα signaling, during tumor progression and metastasis. Therefore, insights into the molecular mechanisms that control ERα expression and stability are of utmost importance to improve breast cancer diagnostics and therapeutics. Here we report that the atypical E3 ubiquitin ligase RNF31 stabilizes ERα and facilitates ERα-stimulated proliferation in breast cancer cell lines. We show that depletion of RNF31 decreases the number of cells in the S phase and reduces the levels of ERα and its downstream target genes, including cyclin D1 and c-myc. Analysis of data from clinical samples confirms correlation between RNF31 expression and the expression of ERα target genes. Immunoprecipitation indicates that RNF31 associates with ERα and increases its stability and mono-ubiquitination, dependent on the ubiquitin ligase activity of RNF31. Our data suggest that association of RNF31 and ERα occurs mainly in the cytosol, consistent with the lack of RNF31 recruitment to ERα-occupied promoters. In conclusion, our study establishes a non-genomic mechanism by which RNF31 via stabilizing ERα levels controls the transcription of estrogen-dependent genes linked to breast cancer cell proliferation.

To detect the relationship between FOXA1 gene polymorphism and type 2 diabetes mellitus (T2DM).The techniques of mass chromatographic analysis were used to detect the polymorphism of FOXA1 gene in 190 patients with T2DM and 193 healthy control persons without T2DM. We used the software SPSS 13.0 for statistical analysis.There was no significant difference between the case and control group about sex and age distribution. The distribution of genotypic frequency in control group consistented with the Hardy-Weinberg law. The frequency of the TT, TC and CC genotype in case were 76.5%, 19.3% and 4.3%. The frequency of the TT, TC and CC genotype in control were 78.1%, 20.3% and 1.6%. There was no significant difference between the case and control group about genotype frequency (chi2 = 2.49, P = 0.287). There may be no significant difference between the TC, TG, HDL-C, LDL-C level and genotypes of rs7144658 in mutant.There may be no significant relationship between the polymorphism of FOXA1 gene and T2DM. Genic mutation on rs7144658 may not affect the lipid level in type 2 diabetics.

Estrogen receptor α (ERα) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERα can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that c-Fos is a fundamental factor for ERα-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent proproliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERα can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross talk between AP-1 and estrogen signaling, we identify a novel ERα/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-β), which is overexpressed in ERα-positive breast cancer tissues. Knockdown of PKIB results in robust growth suppression of breast cancer cells. Collectively, our findings support c-Fos as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.

Triple-negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We show that the AP-1 transcription factor component Fra-1 is overexpressed in basal-like breast tumors, often referred to as TNBCs, and that its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Furthermore, knockdown of Fra-1 or c-Jun also reduces cellular invasion in vivo in a zebrafish xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we provide insights into the transcriptional regulatory networks of AP-1 in TNBC cells. We identify direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Importantly, we show that AP-1 represses E-cadherin expression by transcriptional upregulation of ZEB2, thereby stimulating cell invasion. This work sheds light on mechanisms and pathways by which TNBCs acquire invasiveness and proliferative propensity. Note: This abstract was not presented at the meeting. Citation Format: Chunyan Zhao, Yichun Qiao, Karin Dahlman-Wright. Insights into the invasiveness of triple-negative breast cancer from genome-wide profiling of AP-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1389. doi:10.1158/1538-7445.AM2014-1389

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.