Gene Summary

Gene:HHIP; hedgehog interacting protein
Aliases: HIP
Summary:This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.[provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:hedgehog-interacting protein
Source:NCBIAccessed: 11 August, 2015


What does this gene/protein do?
Show (18)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HHIP (cancer-related)

Shahi MH, Zazpe I, Afzal M, et al.
Epigenetic regulation of human hedgehog interacting protein in glioma cell lines and primary tumor samples.
Tumour Biol. 2015; 36(4):2383-91 [PubMed] Related Publications
Glioma constitutes one of the most common groups of brain tumors, and its prognosis is influenced by different genetic and epigenetic modulations. In this study, we demonstrated low or no expression of hedgehog interacting protein (HHIP) in most of the cell lines and primary glioma tumor samples. We further proceeded to promoter methylation study of this gene in the same cell lines and primary tumor samples and found 87 % (7/8) HHIP methylation in glioblastoma cell lines and 75 % (33/44) in primary tumor samples. These methylation pattern correlates with low or unexpressed HHIP in both cell lines and primary tumor samples. Our results suggest the possibility of epigenetic regulation of this gene in glioma, similarly to medulloblastoma, gastric, hepatic, and pancreatic cancers. Also, HHIP might be a diagnostic or prognostic marker in glioma and help to the detection of these tumors in early stages of disease.

Thathapudi S, Kodati V, Erukkambattu J, et al.
Tumor necrosis factor-alpha and polycystic ovarian syndrome: a clinical, biochemical, and molecular genetic study.
Genet Test Mol Biomarkers. 2014; 18(9):605-9 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Tumor necrosis factor-alpha (TNF-α) appears to be linked with hyperandrogenism (HA), increased insulin resistance (IR), and obesity (Ob), which were common features noted with polycystic ovarian syndrome (PCOS). Our aim was to study the role of TNF-α in the pathogenesis of IR and Ob in PCOS, as well as a C850T (rs1799724) polymorphism in the promoter region of the TNF-α gene, in a group of 204 PCOS patients and 204 age-matched healthy controls.
RESULTS: Significant differences were observed between PCOS patients and controls. All the PCOS had elevated body mass index, waist circumference, waist-to-hip ratio, fasting insulin, homeostatic model assessment (HOMA) score, and serum TNF-α when compared with controls (p<0.05). Genotype distribution for the C-850T polymorphism was observed with the frequency of the variant T allele being 0% in the PCOS group and 9% in the control group (p=0.0032).
CONCLUSIONS: In conclusion, our present results suggest that the TNF-α system might contribute to the pathogenesis of HA, Ob, and IR in PCOS independent of a polymorphism of the TNF-α C850T (rs1799724) in our population.

Chen P, Wang H, Duan Z, et al.
Estrogen-related receptor alpha confers methotrexate resistance via attenuation of reactive oxygen species production and P53 mediated apoptosis in osteosarcoma cells.
Biomed Res Int. 2014; 2014:616025 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Osteosarcoma (OS) is a malignant tumor mainly occurring in children and adolescents. Methotrexate (MTX), a chemotherapy agent, is widely used in treating OS. However, treatment failures are common due to acquired chemoresistance, for which the underlying molecular mechanisms are still unclear. In this study, we report that overexpression of estrogen-related receptor alpha (ERR α ), an orphan nuclear receptor, promoted cell survival and blocked MTX-induced cell death in U2OS cells. We showed that MTX induced ROS production in MTX-sensitive U2OS cells while ERR α effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERR α suppressed ROS induction of tumor suppressor P53 and its target genes NOXA and XAF1 which are mediators of P53-dependent apoptosis. In conclusion, this study demonstrated that ERR α plays an important role in the development of MTX resistance through blocking MTX-induced ROS production and attenuating the activation of p53 mediated apoptosis signaling pathway, and points to ERR α as a novel target for improving osteosarcoma therapy.

Li Z, Park HR, Shi Z, et al.
Pro-oncogenic function of HIP-55/Drebrin-like (DBNL) through Ser269/Thr291-phospho-sensor motifs.
Oncotarget. 2014; 5(10):3197-209 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
HIP-55 (HPK1-interacting protein of 55 kDa, also named DBNL, SH3P7, and mAbp1) is a multidomain adaptor protein that is critical for organ development and the immune response. Here, we report the coupling of HIP-55 to cell growth control through its 14-3-3-binding phospho-Ser/Thr-sensor sites. Using affinity chromatography, we found HIP-55 formed a complex with 14-3-3 proteins, revealing a new node in phospho-Ser/Thr-mediated signaling networks. In addition, we demonstrated that HIP-55 is required for proper cell growth control. Enforced HIP-55 expression promoted proliferation, colony formation, migration, and invasion of lung cancer cells while silencing of HIP-55 reversed these effects. Importantly, HIP-55 was found to be upregulated in lung cancer cell lines and in tumor tissues of lung cancer patients. Upregulated HIP-55 was required to promote the growth of tumors in a xenograft animal model. However, tumors with S269A/T291A-mutated HIP-55, which ablates 14-3-3 binding, exhibited significantly reduced sizes, supporting a vital role of the HIP-55/14-3-3 protein interaction node in transmitting oncogenic signals. Mechanistically, HIP-55-mediated tumorigenesis activity appears to be in part mediated by antagonizing the tumor suppressor function of HPK1. Thus, the HIP-55-mediated oncogenic pathway, through S269/T291, may be exploited for the development of new therapeutic strategies.

Andreassen OA, Zuber V, Thompson WK, et al.
Shared common variants in prostate cancer and blood lipids.
Int J Epidemiol. 2014; 43(4):1205-14 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.
METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.
RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.
CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

Yang C, Li Z, Shi Z, et al.
Regulation of cell survival by the HIP-55 signaling network.
Mol Biosyst. 2014; 10(6):1393-9 [PubMed] Related Publications
HIP-55 (hematopoietic progenitor kinase 1 [HPK1]-interacting protein of 55 kDa) is the mammalian homologue of the yeast Abp1p. It contains a C-terminal Src homology 3 domain and an N-terminal actin depolymerization factor (ADF-H/C) domain. HIP-55 appears to be critical for organ development and immune response and is important for the regulation of the actin cytoskeleton through its interactions with F-actin and various cytoskeletal and cell signaling proteins. However, the function of HIP-55 in tumors remains unknown. Here, we found that HIP-55 is up-regulated or down-regulated in several types of tumor tissues in patients. Of these, lung cancer tissues had the highest expression of HIP-55. To gain full insight into the function of HIP-55 in lung cancer, microarray assay was performed using Affymetrix U133 Plus 2.0 expression arrays in both HIP-55 knockdown and scramble control A549 cells. The ingenuity pathway analysis tool was utilized to construct biological networks and analyze functions that might be associated with HIP-55. Functional analysis strongly suggested that HIP-55 may be involved in cancer cell survival and cell death, which was then confirmed by further experimentation. Experimental results showed that downregulation of HIP-55 decreased the viability and increased the apoptosis of A549 cells treated with the anticancer agent etoposide. Our data suggested that HIP-55 may be a newly discovered regulatory node in the growth signaling network and a new target for therapeutic interventions in proliferative disorders.

Xu L, Shi Y, Gu J, et al.
Association between ghrelin gene variations, body mass index, and waist-to-hip ratio in patients with polycystic ovary syndrome.
Exp Clin Endocrinol Diabetes. 2014; 122(3):144-8 [PubMed] Related Publications
OBJECTIVE: To investigate the association between 2 single nucleotide polymorphisms (SNP501A/C and 604 G/A) in the promoter of the ghrelin gene and the hormonal and metabolic phenotypes of polycystic ovary syndrome (PCOS) in a Chinese population.
MATERIALS AND METHODS: 285 patients with PCOS and 260 healthy controls were selected for a prospective, case-control study at Shandong Provincial Hospital, Jinan, China. All subjects underwent genotype analysis of the 2 single nucleotide polymorphisms of the ghrelin gene. Measurements were also taken of blood lipids, glucose, and hormone levels, and calculations of body mass index (BMI) and waist-to-hip ratio (WHR) were performed to detect hormonal and metabolic phenotypes.
RESULTS: No significant diff erences in polymorphism genotypes were found between PCOS patients and healthy controls. However, the frequency of the -501 A/C A allele was significantly higher in the PCOS group than in the control group. PCOS -501 A/C A carriers had significantly higher BMI and WHR than PCOS women with the CC genotype. -604 G/A polymorphisms were not associated with clinical or biochemical characteristics of PCOS.
CONCLUSIONS: The -501 A/C polymorphism of the ghrelin gene is associated with metabolic features of PCOS in a Chinese population.

Magistri P, Leonard SY, Tang CM, et al.
The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling.
J Surg Res. 2014; 187(2):377-85 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) frequently represents two diseases as it often arises in the setting of cirrhosis caused by the proliferation and activation of hepatic stellate cells (HSCs). Previously, we identified that Hedgehog (Hh) signaling regulates HSC viability and fibrinogenesis, as well as HCC tumorigenesis. Although it is increasingly recognized that HSCs and HCCs communicate via paracrine signaling, Hh's role in this process is just emerging. We hypothesized that a secreted HCC tumor marker and Hh mediator, glypican 3 (GPC3), may regulate HSC.
METHODS: Using three human HCC lines (Hep3B, PLC/PRF/5 and SK-Hep-1) and one Hh-responsive human HSC line (LX-2), we developed two in vitro models of HCC-to-HSC paracrine signaling using a Transwell coculture system and HCC-conditioned media. We then evaluated the effects of these models, as well as GPC3, on HSC viability and gene expression.
RESULTS: Using our coculture and conditioned media models, we demonstrate that the three HCC lines decrease HSC viability. Furthermore, we demonstrate that recombinant GPC3 dose-dependently decreases the LX-2 viability while inhibiting the expression of Hh target genes that regulate HSC viability. Finally, GPC3's inhibitory effects on cell viability and Hh target gene expression are partially abrogated by heparin, a competitor for GPC3 binding.
CONCLUSIONS: For the first time, we show that GPC3, an HCC biomarker and Hh mediator, regulates human HSC viability by regulating Hh signaling. This expands on existing data suggesting a role for tumor-stroma interactions in the liver and suggests that GPC3 plays a role in this process.

Lam UD, Lerchbaum E, Schweighofer N, et al.
Association of MEP1A gene variants with insulin metabolism in central European women with polycystic ovary syndrome.
Gene. 2014; 537(2):245-52 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) shows not only hyperandrogenemia, hirsutism and fertility problems, but also metabolic disturbances including obesity, cardiovascular events and type-2 diabetes. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. We aimed to investigate the association of genetic variants 3'UTR rs17468190 (G/T) of the inflammation-associated gene MEP1A (GenBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women. Genetic variants rs17468190 (G/T) of MEP1A gene were analyzed in 576 PCOS women and 206 controls by using the Taqman fluorogenic 5'-exonuclease assay. This polymorphism was tested for association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. There was a borderline significant difference in genotype distribution between PCOS and control women (p=0.046). In overweight/obese PCOS patients, the variants rs17468190 (G/T) in the MEP1A gene are associated with glucose and insulin metabolism. In a dominant model, the GG genotype of the MEP1A gene was more strongly associated with insulin metabolism in overweight/obese PCOS women (body mass index, BMI>25 kg/m(2)), than in GT+TT genotypes. The MEP1A GG-carriers showed a significantly increased homeostatic model assessment - insulin resistance (HOMA-IR) (p=0.003), elevation of fasting insulin (p=0.004) and stimulated insulin (30 min, p<0.001; 60 min, p=0.009; 120 min, p=0.009) as well as triglyceride (p=0.032) levels. MEP1A is a possible target gene for disease modification in PCOS. It might contribute to the abnormalities of glucose metabolism and insulin sensitivity and serve as a diagnostic or therapeutic target gene for PCOS.

Kimura M, Naito H, Tojo T, et al.
REG Iα gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms.
Oncol Rep. 2013; 30(6):2625-31 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The aim of the present study was to evaluate the effects of the REG Iα and REG Iβ genes on lung cancer cell lines, and thereafter, the expression of REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP and REG IV) in lung cancer in relation to patient prognosis was evaluated. Lung adenocarcinoma (AD) and squamous cell carcinoma (SCC) cell lines expressing REG Iα or REG Iβ (HLC-1 REG Iα/Iβ and EBC-1 REG Iα/Iβ) were established, and cell number, cell invasive activity, and anchorage-independent cell growth were compared with these variables in the control cells. The expression levels of REG family genes were evaluated by real-time RT-PCR in surgically resected lung cancers, and disease-specific survival (DSS) curves were generated. The HLC-1 REG Iα/Iβ cell line showed significant increases in cell number and anchorage-independent cell growth compared with the control cells. EBC-1 REG Iα/Iβ cells showed significant increases in cell invasive activity and anchorage-independent cell growth as compared with the control cells. Except for the REG Iβ gene, expression of other REG family genes was observed in the surgically resected samples; however, DSS was significantly worse only in stage I patients who were positive for REG Iα expression than in patients who were negative for REG Iα expression. The effects of REG Iα on AD and SCC cells were different in the in vitro study, and a correlation between REG Iα expression and patient prognosis was noted in the in vivo study. Therefore, overexpression of REG Iα is a risk factor for poor prognosis caused by discrete mechanisms in AD and SCC patients.

Yang J, Gong H, Liu W, Tao T
The association of Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene with the metabolic characteristics in Chinese women with polycystic ovary syndrome.
Int J Clin Exp Pathol. 2013; 6(9):1894-902 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: The Pro12Ala polymorphism in the peroxisome Proliferator-activated receptor-gamma2 PPARγ2) gene that account for metabolic dysfunction in women with polycystic ovary syndrome (PCOS) remain elusive.
AIM: To explore the association between PPARγ2 gene pro12ala polymorphism and the metabolic characteristics in Chinese women with PCOS.
METHODS: PPARγ2 gene Pro12Ala polymorphism was assayed by PCR/RFLP methods in 120 Chinese women with PCOS and 118 normal subjects. All subjects were examined by anthropometry, lipid profile, sex hormone, oral glucose tolerance tests and insulin tolerance tests.
RESULTS: In PCOS patients, women with the non-Pro/Pro genotypes of the PPARγ2 gene Pro12Ala polymorphism showed statistically significantly higher fasting triglycerides (TG) levels and WHR value than those with the Pro/Pro genotype (P=.006 for both). There was no significant difference with PPARγ2 Pro12Ala polymorphism distributions between Chinese Han women with PCOS and controls.
CONCLUSION: PPARγ2 gene Pro12Ala polymorphism was not supposed to be susceptible genes in PCOS. However, in PCOS patients, the PPAR-gamma Pro12Ala polymorphism may modulate the concentrations of serum fasting TG levels and fat-deposition in abdomen, respectively.

Jia J, Tian Q, Liu Y, et al.
Interactive effect of bisphenol A (BPA) exposure with -22G/C polymorphism in LOX gene on the risk of osteosarcoma.
Asian Pac J Cancer Prev. 2013; 14(6):3805-8 [PubMed] Related Publications
BACKGROUND: Osteosarcomas have many established risk factors, both genetic and environmental, but by themselves these explain only part of the total cancer incidence. Bisphenol A (BPA) is an environmental estrogen associated with risk of several kinds of tumour. The lysyl oxidase gene (LOX) may also contribute to risk of tumours including osteosarcomas. Here, we investigated possible interactions of BPA and a LOX polymorphism on the risk of osteosarcoma.
METHOD: The present hospital-based case-control study included 106 cancer patients and 112 controls from a Chinese population. Internal burden of BPA exposure was assessed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) method. Genotypes were determined using PCR-RFLP methods.
RESULTS: Compared with those in low BPA exposure group, subjects with BPA more than or equal to median value had significant increased risk of osteosarcoma among subjects who carried GC or CC genotypes. A significant interaction with BPA level and the -22 G/C polymorphism was observed for osteosarcoma overall, osteosarcoma affecting knee and osteosarcoma affecting hip, as P(forinteraction) = 0.036 for osteosarcoma overall; P(forinteraction) = 0.024 for osteosarcoma affecting knee; and P(forinteraction) = 0.017 for osteosarcoma affecting hip.
CONCLUSIONS: The results suggest that BPA exposure interacts with the -22 G/C polymorphism of the LOX gene to increase the risk of osteosarcoma.

Zhuang Z, Wang K, Cheng X, et al.
LKB1 inhibits breast cancer partially through repressing the Hedgehog signaling pathway.
PLoS One. 2013; 8(7):e67431 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1. In contrast, LKB1 siRNA increased the expression of these target genes. The same results were shown to inhibit the Hh factors Sufu and Hip. Furthermore, we also observed negative correlation between LKB1 and glioma-associated oncogene homologue 1 (GLI1) in three breast cancer cell lines. Meanwhile, LKB1 siRNA rescued the inhibition of cell growth by 3-Keto-N-(aminoethyl-N'-aminocaproyldihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), an antagonist of the Hh element SMO, which suggests that LKB1 acts as the downstream of SMO. In vivo, LKB1 siRNA increased tumor growth in the mammary fat pad, and the expression levels of Hh displayed similar results in vitro. Overexpression of the LKB1 protein in human breast cancers is associated with the expression of Hh. We found that breast carcinomas with detectable Hh had weak or undetectable expression of LKB1, whereas tumors that expressed high levels of LKB1 had undetectable Hh signaling. In this study, we find that LKB1 are negatively correlated with the expression of Hh related transcription factors. These findings suggest that LKB1 may inhibit tumorigenesis by regulating Hh signaling in certain cancers.

Edwards TL, Giri A, Motley S, et al.
Pleiotropy between genetic markers of obesity and risk of prostate cancer.
Cancer Epidemiol Biomarkers Prev. 2013; 22(9):1538-46 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer and genetic markers of obesity and metabolism.
METHODS: Analyses included 176,520 single-nucleotide polymorphisms (SNP) associated with 23 metabolic traits. We examined the association between SNPs and prostate cancer in 871 cases and 906 controls, including 427 high-grade cases with Gleason ≥ 7. Genetic risk scores (GRS) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR.
RESULTS: Prostate cancer was associated with five loci, including cyclin M2, with P values less than 1 × 10(-4). In addition, the WHR GRS was associated with high-grade prostate cancer versus controls [OR, 1.05; 95% confidence interval (CI), 1.00-1.11; P = 0.048] and high-grade prostate cancer versus low-grade prostate cancer (OR, 1.07; 95% CI, 1.01-1.13; P = 0.03). None of these findings exceeds the threshold for significance after correction for multiple testing.
CONCLUSIONS: Variants in genes known to be associated with metabolism and obesity may be associated with prostate cancer. We show evidence for pleiotropy between WHR GRS and prostate cancer grade. This finding is consistent with the function of several WHR genes and previously described relationships with cancer traits.
IMPACT: Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in prostate cancer. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples.

Götschel F, Berg D, Gruber W, et al.
Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.
PLoS One. 2013; 8(6):e65403 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.

Liu HW, Zhang F, Fan P, et al.
Effects of apolipoprotein E genotypes on metabolic profile and oxidative stress in southwest Chinese women with polycystic ovary syndrome.
Eur J Obstet Gynecol Reprod Biol. 2013; 170(1):146-51 [PubMed] Related Publications
OBJECTIVE: Apolipoprotein (APO) E genetic polymorphism plays an important role in lipid and lipoprotein metabolism, and has been shown to be associated with the risk of metabolic and cardio-cerebrovascular diseases and late-onset Alzheimer's disease. It is not clear, however, whether there are any relationships between the APOE genotypes and PCOS in Chinese women. The aim of this study was to investigate the relationship between APOE genotypes and the risk of polycystic ovary syndrome (PCOS) and to evaluate the effects of the genotypes on metabolic profile and oxidative stress in south-west Chinese women.
STUDY DESIGN: A total of 625 patients with PCOS based on the Rotterdam consensus criteria and 514 control women from a population of Chinese Han nationality in the Chengdu area were studied during 2006-2012. APOE genotypes were determined by PCR and restriction fragment length polymorphism analysis. Clinical and metabolic parameters, serum malondialdehyde concentration, and total antioxidant capacity were analyzed.
RESULTS: No significant differences were found in the frequencies of APOE genotypes (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) and alleles (ε2, ε3, ε4) between PCOS and control groups. Compared with ε3 homozygotes (APOE3/3), however, ε2 carriers (APOE2/2+APOE2/3+APOE2/4) had significantly higher body mass index, waist circumference and waist-to-hip ratio, a more adverse glucose and insulin metabolic profile, lower high density lipoprotein (HDL)-cholesterol (C) and APOA1 levels, higher triglyceride (TG)/HDL-C ratio and prevalence of metabolic syndrome (MS), whereas ε4 carriers (APOE3/4+APOE4/4) had higher total cholesterol (TC) and low density lipoprotein (LDL)-C levels in patients with PCOS.
CONCLUSIONS: In a cohort of south-west Chinese women, there were no significant associations between any APOE genotype and PCOS. The APOE ε2 allele seems to be related to abdominal obesity, insulin resistance and MS in PCOS women.

Napoli N, Rastelli A, Ma C, et al.
Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER + breast cancer.
Bone. 2013; 55(2):309-14 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE: Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer.
PATIENTS AND METHODS: The subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay.
RESULTS: Women with the AA genotype for the rs700518 (G/A at Val(80)) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p = 0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p = 0.05; but no significant difference in changes in estradiol levels among the genotypes.
CONCLUSION: Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.

Song Y, Tian Y, Zuo Y, et al.
Altered expression of PTCH and HHIP in gastric cancer through their gene promoter methylation: novel targets for gastric cancer.
Mol Med Rep. 2013; 7(4):1159-68 [PubMed] Related Publications
Human hedgehog-interacting protein (HHIP) and protein patched homolog (PTCH) are two negative regulators of the hedgehog signal, however, the mechanism of action in gastric cancer is unknown. Methylation of TSG promoters has been considered as a causative mechanism of tumorigenesis. In the present study, we first determined the expression of PTCH and HHIP mRNA and protein in gastric cancer tissues and adjacent normal tissues, and then detected methylation of the two genes to associate their expression and gene promoter methylation in gastric cancer. Expression in gastric cancer tissues and the cancer cells (AGS) were evaluated by reverse transcription-PCR (RT-PCR), qRT-PCR and IHC, while the methylation expression was valued by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). Cell viability and apoptosis were analyzed by MTT assay and flow cytometry following treatment with 5-aza-dc. Results showed that PTCH and HHIP expression was reduced in gastric cancer tissues that were not associated with clinical features. Moreover, methylation of the promoters was reversely correlated with the expression. Following treatment with 5-aza-dc, AGS reduced cell viability and induced apoptosis, which is associated with upregulation of HHIP expression. The data demonstrated that loss of expression of HHIP and PTCH is associated with the methylation of gene promoters. In addition, 5-aza-dc-induced apoptosis correlated with the upregulation of HHIP expression in AGS. The findings demonstrated that the PTCH and HHIP genes may be novel targets for the control of gastric cancer.

Deepika ML, Reddy KR, Rani VU, et al.
Do ACE I/D gene polymorphism serve as a predictive marker for age at onset in PCOS?
J Assist Reprod Genet. 2013; 30(1):125-30 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disorder exhibiting variable age at onset of clinical features allied with complex diseases in the later life. ACE is a pleiotropic molecule associated with various pathophysiological functions. The present study was aimed to establish the frequency of ACE I/D gene polymorphism in patients and controls and to assess the influence of this polymorphism on anthropometric and various clinical features of the condition.
METHODS: ACE I/D genotyping was carried out in 259 PCOS patients and 315 healthy ultrasound scanned women of South Indian origin.
RESULTS: The distribution of DD, ID and II genotypes in patients was 39, 37 and 24 %, whereas in the controls it was 31, 51 and 18 % respectively. Significant difference was observed in the genotypic frequency distributions between the patients and controls, however the allelic frequencies did not vary between the groups (p>0.05). Quartile analysis revealed preponderance of DD genotype in the first two quartiles and a linear increase of II genotype from first to the last quartiles. Further, Multiple Logistic regression analysis revealed significant association of ACE I/D gene polymorphism with acanthosis and age at onset (AAO) of the syndrome (p<0.05).
CONCLUSION: The present study is the first report to highlight the predisposing role of DD and protective role of ID genotype towards PCOS. Patients with single or double dose of D allele may develop PCOS symptoms at an early age and also significantly associated with acanthosis, a marker of insulin resistance.

Li H, Beeghly-Fadiel A, Wen W, et al.
Gene-environment interactions for breast cancer risk among Chinese women: a report from the Shanghai Breast Cancer Genetics Study.
Am J Epidemiol. 2013; 177(2):161-70 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Genome-wide association studies have identified approximately 20 susceptibility loci for breast cancer. A cumulative genetic risk score (GRS) was constructed from 10 variants with replicated associations among participants of the Shanghai Breast Cancer Genetics Study (Shanghai, China, 1996-1998 and 2002-2005). Interactions between the GRS and 11 breast cancer risk factors were evaluated. Among the 6,408 study participants, no evidence of effect modification was found with the GRS for age at menarche, age at menopause, age at first live birth/parity, total months of breastfeeding, family history of breast cancer, history of benign breast disease, hormone replacement therapy, body mass index, waist/hip ratio, or regular physical activity. The effect of the GRS was least homogeneous by duration of menstruation; further analysis indicated a nominally significant interaction with one genetic variant. The mitochondrial ribosomal protein S30 gene (MRPS30) rs10941679 was associated with breast cancer risk only among women with more than 30 years of menstruation (odds ratio = 1.15, 95% confidence interval: 1.05, 1.26). Although this multiplicative interaction reached a nominal significance level (P = 0.037), it did not withstand correction for multiple comparisons. In conclusion, this study revealed no apparent interactions between genome-wide association study-identified genetic variants and breast cancer risk factors in the etiology of this common cancer.

Levin GP, Robinson-Cohen C, de Boer IH, et al.
Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.
JAMA. 2012; 308(18):1898-905 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.
OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.
MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.
RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.
CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

Bai R, Shi Z, Zhang JW, et al.
ST13, a proliferation regulator, inhibits growth and migration of colorectal cancer cell lines.
J Zhejiang Univ Sci B. 2012; 13(11):884-93 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND AND OBJECTIVE: ST13, is the gene encoding the HSP70 interacting protein (HIP). Previous research has shown that ST13 mRNA and protein levels are down-regulated in colorectal cancer (CRC) tissues compared with adjacent normal tissues. This study aims at the role of ST13 in the proliferation and migration of CRC cells.
METHODS: The transcript level of ST13 in different CRC cell lines was evaluated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). ST13-overexpressed and ST13-knockdown CRC cells were constructed respectively by lentiviral transduction, followed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, plate colony formation, cell-cycle analysis, and migration assays to evaluate the influence of ST13 on proliferation and migration in vitro. Moreover, a mouse xenograft study was performed to test in vivo tumorigenicity of ST13-knockdown CRC cells.
RESULTS: Lentivirus-mediated overexpression of ST13 in CRC cells inhibited cell proliferation, colony formation, and cell migration in vitro. In contrast, down-regulation of ST13 by lentiviral-based short hairpin RNA (shRNA) interference in CRC cells significantly increased cell proliferation and cloning efficiency in vitro. In addition, down-regulation of ST13 expression significantly increased the tumorigenicity of CRC cells in vivo.
CONCLUSIONS: ST13 gene is a proliferation regulator that inhibits tumor growth in CRC and may affect cell migration.

Shahi MH, Rey JA, Castresana JS
The sonic hedgehog-GLI1 signaling pathway in brain tumor development.
Expert Opin Ther Targets. 2012; 16(12):1227-38 [PubMed] Related Publications
INTRODUCTION: The sonic hedgehog (Shh) pathway is a regulatory network involved in development and cancer. Proteins like Ptch, SMO, and Gli are central to the Shh pathway. Other proteins like HHIP, SUFU, Bmi-1, Cyclin D2, Plakoglobin, PAX6, Nkx2.2, and SFRP1 are not so well understood in Shh regulation as Gli-1 downstream target genes.
AREAS COVERED: In this review we try to explain the Shh pathway components and their role in development and cancer, mainly of the brain. A summary of each of the proteins is presented together with an overview of their involvement in cancer.
EXPERT OPINION: Genetic alterations of the Shh pathway have been detected in cancer stem cells, a subgroup of tumor cells implicated in the origin and maintenance of tumors, being responsible for cancer recurrence and chemotherapy resistance. Cancer stem cells constitute a novel target for biomedical researchers. Specifically, the Shh pathway is being explored as a new opportunity for targeted therapies against tumors. Therefore, a better knowledge of every of the regulators of the Shh pathway is needed.

Medina Villaamil V, Aparicio Gallego G, Santamarina Caínzos I, et al.
Searching for Hif1-α interacting proteins in renal cell carcinoma.
Clin Transl Oncol. 2012; 14(9):698-708 [PubMed] Related Publications
INTRODUCTION: Kidney tumours are frequently characterised by hypoxic conditions due to a local imbalance between oxygen (O2) supply and consumption. Hif1-α regulates angiogenesis, tumour growth, tumour progression, metastatic spread, and glucose metabolism by acting as a transcription factor for relevant genes. Here, we describe an immunohistochemical study of Hif1-α, a comprehensive computational study of Hif1-α interacting proteins (HIPs), an analysis correlating expression levels of Hif1-α with upstream and downstream proteins, and an analysis of the utility of Hif1-α for prognosis in a cohort of patients with renal cell carcinoma.
MATERIALS AND METHODS: The patient cohort included 80 patients. For immunohistochemistry evaluation, tissue microarrays were constructed. The IntAct, MINT, and BOND databases were used for the HIP approach. The Kruskal-Wallis test was used for comparing protein expression with pathology measurements. Correlation was expressed as the Pearson coefficient.
RESULTS: Hif1-α expression correlates significantly with the "clear" histological subtype of renal cell carcinoma (p < 0.01). The samples with the worst prognoses related to the pathological variables analysed showed the highest levels of Hif1-α expression. Significant correlations were found with Bcl-2, CAIX, C-kit, EGFR, TGF-β, proteins of the VEGF family, proteins related to differentiation (such as Notch1 and Notch3) and certain metabolic enzymes. Bioinformatic analysis suggested 45 evidence-based HIPs and 4 complexes involving protein Hif1-α.
CONCLUSIONS: This work summarises the multifaceted role of Hif1-α in the pathology of renal cell carcinomas, and it identifies HIPs that could help provide mechanistic explanations for the different behaviours seen in tumours.

Yang Q, Shen SS, Zhou S, et al.
STAT3 activation and aberrant ligand-dependent sonic hedgehog signaling in human pulmonary adenocarcinoma.
Exp Mol Pathol. 2012; 93(2):227-36 [PubMed] Related Publications
The Sonic hedgehog (SHH) signaling and STAT3 pathways play important roles during carcinogenesis with possible interaction. To determine the association of the activation of SHH signaling pathway and STAT3 pathway in carcinogenesis of human non-small cell lung carcinomas (NSCLC), firstly we examined the expression of SHH signaling molecules including SHH, Gli1(glioma-associated oncogene homolog 1) and HHIP (Hh interacting protein), as well as p-STAT3 (phosphorylation at Tyr705) by immunohistochemistry in 87 cases of NSCLC, 12 atypical adenomatous hyperplasia (AAH) and 20 adjacent normal lung tissues. The expression of SHH, Gli1, HHIP and p-STAT3 was detected respectively in 87/87(100%), 74/87(85.1%), 75/87(86.2%) and 54/87(62.1%) of the NSCLC cases, but not in the adjacent normal lung parenchyma. Ligand-dependent SHH pathway activation and STAT3 signaling activation were observed in most cases of NSCLC, and the high SHH pathway activation rate and STAT3 activation rate were significantly higher in adenocarcinoma compared with squamous cell carcinomas and large cell carcinomas (P<0.05). Both SHH and STAT3 pathway activation level correlated with histological grade in adenocarcinoma, being higher in well-differentiated types (P<0.05). Furthermore, high SHH pathway activation and p-STAT3 expression were also detected in 10/12(83.3%) of AAH cases as well as in most cases of early-stage adenocarcinoma - adenocarcinoma in situ (AIS) and minimally invasive adenocarcinomas (MIA). Correlation analysis showed that p-STAT3 protein expression level was correlated positively with ligand-dependent activation level of SHH signaling in adenocarcinoma (r(s)=0.585, P=0.000) and AAH (r(s)=0.996, P=0.000). We speculated that activation of STAT3 could up-regulate SHH gene expression directly or indirectly, and thereby activated SHH signaling resulting in lung tumor cell ontogeny. To explore the interactional mechanism, we then performed serial transient co-transfection assay in human pulmonary adenocarcinoma cell line H441 cells, and the results confirmed STAT3 activation can up-regulate SHH gene expression indirectly. In conclusion, aberrant ligand-dependent SHH signaling activation occurs frequently in NSCLC. The signaling plays a more active role in adenocarcinoma, and is an early event in carcinogenesis of lung adenocarcinoma. The involvement of STAT3 pathway activation might function in inducing the process.

van Dop WA, Rosekrans SL, Uhmann A, et al.
Hedgehog signalling stimulates precursor cell accumulation and impairs epithelial maturation in the murine oesophagus.
Gut. 2013; 62(3):348-57 [PubMed] Related Publications
OBJECTIVE: In the intestine Hedgehog (Hh) signalling is directed from epithelium to mesenchyme and negatively regulates epithelial precursor cell fate. The role of Hh signalling in the oesophagus has not been studied in vivo. Here the authors examined the role of Hh signalling in epithelial homeostasis of oesophagus.
DESIGN: The authors used transgenic mice in which the Hh receptor Patched1 (Ptch1) could be conditionally inactivated in a body-wide manner and mice in which Gli1 could be induced specifically in the epithelium of the skin and oesophagus. Effects on epithelial homeostasis of the oesophagus were examined using immunohistochemistry, in situ hybridisation, transmission electron microscopy and real-time PCR. Hh signalling was examined in patients with oesophageal squamous cell carcinoma (SCC) by quantitative real-time PCR.
RESULTS: Sonic Hh is signalled in an autocrine manner in the basal layer of the oesophagus. Activation of Hh signalling resulted in an expansion of the epithelial precursor cell compartment and failure of epithelial maturation and migration. Levels of Hh targets GLI1, HHIP and PTCH1 were increased in SCC compared with normal tissue from the same patients.
CONCLUSION: Here the authors find that Hh signalling positively regulates the precursor cell compartment in the oesophageal epithelium in an autocrine manner. Since Hh signalling targets precursor cells in the oesophageal epithelium and signalling is increased in SCCs, Hh signalling may be involved in oesophageal SCC formation.

Bosviel R, Garcia S, Lavediaux G, et al.
BRCA1 promoter methylation in peripheral blood DNA was identified in sporadic breast cancer and controls.
Cancer Epidemiol. 2012; 36(3):e177-82 [PubMed] Related Publications
OBJECTIVE: Epigenetics, particularly DNA methylation, has recently been shown to be important in breast cancer initiation. We investigated the clinical and prognostic importance of whole blood breast cancer early onset gene 1 (BRCA1) DNA methylation in sporadic breast cancer.
METHODS: Genomic DNA was extracted from the peripheral blood cells (PBCs) of 902 breast cancer patients at diagnosis, with no BRCA1 mutation, and 990 control women. DNA methylation was measured by quantitative analysis of methylated alleles (QAMA) to estimate the extent of methylation of 2 CpG sites in the promoter region of BRCA1 oncosuppressor.
RESULTS: BRCA1 promoter methylation rate in PBCs was 47.1% with a 95% confidence interval [46.1; 48.1] in breast cancer patients, and 45.9% with a 95% confidence interval [45.0; 46.8] in controls. We found a trend toward BRCA1 promoter hypermethylation in PBCs of sporadic breast cancer patients compared with controls. Association between methylation and clinicopathological features was evaluated using statistical tests. BRCA1 promoter methylation in PBCs increased significantly in breast cancer patients compared with controls, for age over 70 years (p=0.022), in post-menopausal status (p=0.013), for a body mass index (BMI) <20 (p=0.0095) or a waist-to-hip ratio (WHR) ≤76.8 (p=0.0027). We also found an association of increased BRCA1 promoter methylation in PBCs with ACA/ACA genotype for the SNP Thr594Thr in ESR (estrogen receptor gene), known to be associated with breast cancer risk (p=0.092), reflecting the reduced presence of this genotype in this breast cancer case-control study.
CONCLUSION: Analysis of site-specific DNA methylation in PBCs by QAMA provides quantitative DNA methylation values that may serve as important prognostic indicators.

Xue F, Li S, Luan J, et al.
A latent variable partial least squares path modeling approach to regional association and polygenic effect with applications to a human obesity study.
PLoS One. 2012; 7(2):e31927 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609∼rs9939881 at the first intron P = 4.29×10(-7)) than single SNP analysis (all with P>10(-4)) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits.

Keating GL, Turner EC, Kinsella BT
Regulation of the human prostacyclin receptor gene in megakaryocytes: major roles for C/EBPδ and PU.1.
Biochim Biophys Acta. 2012; 1819(5):428-45 [PubMed] Related Publications
The prostanoid prostacyclin plays a central role in haemostasis and vascular repair. Recent studies investigating the regulation of the human prostacyclin receptor (hIP) gene identified an upstream repressor region (URR) within its regulatory promoter, herein termed the PrmIP. This study aimed to identify the main trans-acting factors that bind within the URR to transcriptionally repress PrmIP-directed gene expression in the megakaryoblastic human erythroleukemia (HEL) 92.1.7 cell line. Of the putative cis-acting elements examined, disruption of C/EBP and PU.1 elements within the URR substantially increased PrmIP-directed gene expression. Chromatin immunoprecipitation (ChIP) confirmed that C/EBPδ and PU.1, but not C/EBPβ, bind to the URR in vivo, while ectopic expression of C/EBPδ substantially reduced hIP mRNA levels and PrmIP-directed gene expression. Phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation increased hIP mRNA and PrmIP-directed reporter gene expression and hIP-mediated cAMP generation in HEL cells. Two PMA-responsive regions, termed PRR1 and PRR2, were identified within PrmIP. Disruption of C/EBPδ and PU.1 cis-elements within the overlapping PRR1/URR and of Sp1, PU.1 and Oct-1 cis-elements within the overlapping PRR2/core PrmIP, revealed that both PRR1 and PRR2 contribute to the PMA- induction of hIP mRNA and gene expression in HEL cells. Furthermore, ChIP analysis established that induction of PrmIP-directed gene expression during megakaryocytic differentiation is largely regulated by PMA-induced dissociation of C/EBPδ and enhanced binding of PU.1 to PRR1 in addition to increased binding of Sp1, PU.1 and Oct-1 to elements within the core promoter/PRR2 in vivo. Taken together, these data provide critical insights into the transcriptional regulation of the hIP gene within the vasculature, including during megakaryocytic differentiation.

Wang Y, Liu H, Fan P, et al.
Evidence for association between paraoxonase 1 gene polymorphisms and polycystic ovarian syndrome in southwest Chinese women.
Eur J Endocrinol. 2012; 166(5):877-85 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to investigate the relationship between 192Q/R and 55L/M polymorphisms of paraoxonase 1 (PON1) gene and polycystic ovarian syndrome (PCOS) in Chinese women.
DESIGN: A case-control study.
METHODS: A total of 1113 subjects (610 patients with PCOS and 503 control women) from a population of Chinese Han nationality in Chengdu area were included in this study. PON1 genotypes were studied using PCR and restriction fragment length polymorphism analysis. Clinical and metabolic parameters were analyzed.
RESULTS: The frequencies of PON1 192RR genotype and R allele were significantly higher in patients with PCOS than in control women (44.6 vs 36.4%, 0.667 vs 0.610 respectively). The 192RR genotype remained a significant predictor for PCOS (odds ratio (RR/QR)(+)(QQ): 1.656, 95% confidence interval: 1.156-2.371) in prognostic models including age, body mass index, insulin resistance index, triglyceride, HDL, and LDL as covariates. Compared with patients with QQ genotype, patients with RR or QR genotype had significantly higher waist circumference and fasting insulin and triglyceride levels, patients with RR genotype had significantly higher waist-to-hip ratio, and patients with QR genotype had significantly higher homeostasis model assessment of insulin resistance. Such relationships were not detected in the control women. No significant differences were found in the frequencies of PON1 55L/M genotype and allele between PCOS and control groups.
CONCLUSIONS: The 192Q/R, but not 55L/M, polymorphism in PON1 gene is associated with the risk of PCOS in south-west Chinese women.

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