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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hedgehog-interacting protein
Source:NCBIAccessed: 16 March, 2017


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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 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)

Niramitmahapanya S, Deerochanawong C, Sarinnapakorn V, et al.
Somatic HRPT2 Mutation (Arg234X) of Parathyroid Carcinoma Associated with Slipped Capital Femoral Epiphysis: A First Case Report.
J Med Assoc Thai. 2016; 99 Suppl 2:S201-5 [PubMed] Related Publications
A 14-year-old boy was admitted to the orthopedic clinic of Rajavithi Hospital complaining of pain in the left hip. A year earlier, pain had developed in his left joint and had gradually increased in intensity in both hips. A month before he was referred, radiographs obtained at another hospital showed bilateral slipped capital femoral epiphysis (SCFE). The patient's biochemical laboratory data showed hypercalcemia, hypophosphatemia, and a high level of intact parathyroid hormone (iPTH) compatible with primary hyperparathyroidism. HRPT2 gene analysis found heterozygosity for c. 700 C > T mutation (Arg234X) of HRPT2 gene at exon 7. This is the first report in the literature about somatic mutation of the HRPT2 gene of parathyroid carcinoma associated with slipped capital femoral epiphysis.

Shafiee MN, Seedhouse C, Mongan N, et al.
Up-regulation of genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link polycystic ovarian syndrome and endometrial cancer.
Mol Cell Endocrinol. 2016; 424:94-101 [PubMed] Related Publications
BACKGROUND: Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (EC) risk compared to women without PCOS, the precise molecular mechanisms which link between PCOS and EC remain unclear. It has been suggested that insulin resistance may contribute to the increased risk of EC in PCOS. The specific expression of genes related to the insulin-signalling pathway including the IGF system in the endometrium of women with PCOS has however never been measured and compared to that in women with EC without PCOS and control women without EC or PCOS. .
OBJECTIVES: To test the hypothesis that insulin signalling plays a key role in the development of EC in women with PCOS by measuring and comparing the expression of three key genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in endometrial tissue obtained from three groups of women; PCOS without EC, women with EC without PCOS and non-PCOS women without EC (controls). We also aimed to determine the correlation between the gene expressions to various clinical variables among participants.
METHODS: This was a cross-sectional study of 102 women in 3 groups (PCOS, EC and controls) at a University teaching hospital in the United Kingdom. Clinical assessment (blood pressure, body mass index (BMI) and waist-hip-circumference ratio), venepuntures (fasting blood sugar, insulin, lipid profile, hormones) and endometrial tissue biopsies were taken in all participants. Endometrial tissue RNA extraction was performed before real time polymerase-chain-reaction for the genes of interest (IGF1, IGFBP1 and PTEN) was carried out. To compare the baseline characteristics of the study population, One-Way-ANOVA test or the Independent t-test was used. For variables that were not normally distributed, the Spearman correlation test was used to calculate the r value. A "p" value of <0.05 was considered statistically significant.
RESULTS: IGF1, IGFBP1 and PTEN gene expression were significantly up-regulated in the endometrium of PCOS and EC women compared to controls. However there was no significant difference in the expression of these genes in PCOS compared to EC endometrium. The BMI of women with PCOS and controls, were not significantly different (29.28 (± 2.91) vs 28.58 (± 2.62) kg/m(2)) respectively, women with EC however had a higher mean BMI (32.22 (± 5.70) kg/m(2)). PCOS women were younger (31.8 (± 5.97) years) than women with EC (63.44 (± 10.07) years) and controls (43.68 (± 13.12) years). The changes in gene expression were independent of BMI, waist hip ratio, estradiol and androgen levels. Protein validation test in the serum samples in the three groups were consistent with the gene findings.
CONCLUSION: Women with PCOS and EC have an increased endometrial expression of genes (IGF1, IGFBP1 and PTEN) involved in the insulin signalling pathway compared with control women. This may explain the increased risk of EC in PCOS women. This study provides a strong basis for clinical trials aiming to prevent EC in women with PCOS by investigating drugs targeting the insulin signalling pathway. This panel of genes may also serve as clinically useful early biomarkers which predict which women with PCOS will go on to develop EC.

Yavropoulou MP, Maladaki A, Topouridou K, et al.
Expression pattern of the Hedgehog signaling pathway in pituitary adenomas.
Neurosci Lett. 2016; 611:94-100 [PubMed] Related Publications
Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged-1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway.

Ek WE, Lagergren K, Cook M, et al.
Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.
Int J Cancer. 2016; 138(5):1146-52 [PubMed] Free Access to Full Article Related Publications
The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

Ochs-Balcom HM, Marian C, Nie J, et al.
Adiposity is associated with p53 gene mutations in breast cancer.
Breast Cancer Res Treat. 2015; 153(3):635-45 [PubMed] Related Publications
Mutations in the p53 gene are among the most frequent genetic events in human cancer and may be triggered by environmental and occupational exposures. We examined the association of clinical and pathological characteristics of breast tumors and breast cancer risk factors according to the prevalence and type of p53 mutations. Using tumor blocks from incident cases from a case-control study in western New York, we screened for p53 mutations in exons 2-11 using the Affymetrix p53 Gene Chip array and analyzed case-case comparisons using logistic regression. The p53 mutation frequency among cases was 28.1 %; 95 % were point mutations (13 % of which were silent) and the remainder were single base pair deletions. Sixty seven percent of all point mutations were transitions; 24 % of them are G:C>A:T at CpG sites. Positive p53 mutation status was associated with poorer differentiation (OR, 95 % CI 2.29, 1.21-4.32), higher nuclear grade (OR, 95 % CI 1.99, 1.22-3.25), and increased Ki-67 status (OR, 95 % CI 1.81, 1.10-2.98). Cases with P53 mutations were more likely to have a combined ER-positive and PR-negative status (OR, 95 % CI 1.65, 1.01-2.71), and a combined ER-negative and PR-negative status (OR, 95 % CI 2.18, 1.47-3.23). Body mass index >30 kg/m(2), waist circumference >79 cm, and waist-to-hip ratio >0.86 were also associated with p53 status; obese breast cancer cases are more likely to have p53 mutations (OR, 95 % CI 1.78, 1.19-2.68). We confirmed that p53 mutations are associated with less favorable tumor characteristics and identified an association of p53 mutation status and adiposity.

Jorde R, Schirmer H, Wilsgaard T, et al.
The DBP Phenotype Gc-1f/Gc-1f Is Associated with Reduced Risk of Cancer. The Tromsø Study.
PLoS One. 2015; 10(5):e0126359 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVE: In addition to its role as a transport protein, the vitamin D binding protein (DBP) may also affect lipid metabolism, inflammation and carcinogenesis. There are three common variants of the DBP, Gc1s (1s), Gc1f (1f), Gc2 (2) that result in six common phenotypes (1s/1s, 1s/1f, 1s/2, 1f/1f, 1f/2, and 2/2). These phenotypes can be identified by genotyping for the two single nucleotide polymorphisms rs7041 and rs4588 in the GC gene. The DBP variants have different binding coefficients for the vitamin D metabolites, and accordingly there may be important relations between DBP phenotypes and health.
METHODS: DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2010- 2013. Genotyping was performed for rs7041 and rs4588 and serum 25-hydroxyvitamin D (25(OH)D) was measured.
RESULTS: Genotyping for rs7041 and rs4588 was performed successfully in 11 704 subjects. Among these, 1660 were registered with incident MI, 958 with T2DM, 2410 with cancer and 4318 had died. Subjects with the DBP phenotype 1f/1f had 23 - 26 % reduced risk of incident cancer compared to the 1s/1s and 2/2 phenotypes (P < 0.02, Cox regression with gender as covariate). Differences in serum 25(OH)D levels could not explain the apparent cancer protective effect of the DBP variant 1f. In addition to cancer and 25(OH)D, there were significant associations between DBP phenotype and body height, hip circumference and serum calcium.
CONCLUSION: There are important biological differences between the common DBP phenotypes. If the relation between the DBP variant 1f and cancer is confirmed in other studies, determination of DBP phenotype may have clinical importance.

Guerra L, Fortugno P, Sinistro A, et al.
Betapapillomavirus in multiple non-melanoma skin cancers of Netherton syndrome: Case report and published work review.
J Dermatol. 2015; 42(8):786-94 [PubMed] Related Publications
Netherton syndrome (NS) is a rare genetic disease presenting with ichthyosiform erythroderma, hair alterations and atopy. NS is due to SPINK5 gene mutations, which cause absent or decreased expression of the encoded protein lymphoepithelial Kazal-type-related inhibitor (LEKTI) in all stratified epithelia. We report a 43-year-old man affected with NS, who developed several squamous and basal cell carcinomas on the face, ears and scalp and papillomatous lesions of hips, groin and genitoanal area. Molecular analysis of the SPINK5 gene revealed homozygosity for the recurrent mutation c.238dupG. Human papillomavirus (HPV) DNA detection and genotyping on patient skin carcinomas and hyperplastic lesions found betapapillomavirus DNA in 10 of 12 (83%) carcinomas and in a hip papilloma, with multiple betapapillomavirus types being identified. Immunohistochemistry showed upregulated expression of p16(INK4a) protein in nine of 12 (75%) patient carcinomas, in line with findings reported in HPV-related cancers. LEKTI and filaggrin immunostaining was strongly decreased in patient skin. A published work search for NS cases with skin cancers and HPV infection identified 15 NS patients, five of them showing mucosal or cutaneous HPV infection. Overall, our results confirm the increased susceptibility to skin carcinomas of some NS patients and provide further evidence of an association between HPV and non-melanoma skin cancers in NS. The highly impaired skin barrier function, hallmark of NS, could facilitate HPV infection, in turn increasing the risk for cancer development.

Ribero S, Glass D, Aviv A, et al.
Height and bone mineral density are associated with naevus count supporting the importance of growth in melanoma susceptibility.
PLoS One. 2015; 10(1):e0116863 [PubMed] Free Access to Full Article Related Publications
Naevus count is the strongest risk factor for melanoma. Body Mass Index (BMI) has been linked to melanoma risk. In this study, we investigate the link between naevus count and height, weight and bone mineral density (BMD) in the TwinsUK cohort (N = 2119). In addition we adjusted for leucocyte telomere length (LTL) as LTL is linked to both BMD and naevus count. Naevus count was positively associated with height (p = 0.001) but not with weight (p = 0.187) despite adjusting for age and twin relatedness. This suggests that the previously reported melanoma association with BMI may be explained by height alone. Further adjustment for LTL did not affect the significance of the association between height and naevus count so LTL does not fully explain these results. BMD was associated with naevus count at the spine (coeff 18.9, p = 0.01), hip (coeff = 18.9, p = 0.03) and forearm (coeff = 32.7, p = 0.06) despite adjusting for age, twin relatedness, weight, height and LTL. This large study in healthy individuals shows that growth via height, probably in early life, and bone mass are risk factors for melanoma via increased naevus count. The link between these two phenotypes may possibly be explained by telomere biology, differentiation genes from the neural crests but also other yet unknown factors which may influence both bones and melanocytes biology.

Thathapudi S, Kodati V, Erukkambattu J, et al.
Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome.
Genet Test Mol Biomarkers. 2015; 19(3):128-32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovaries and irregular menstruation/anovulation are important diagnostic criteria along with hyperandrogenism as per the Androgen Excess Society-2006 criteria for polycystic ovarian syndrome (PCOS). In the etiopathogenesis of PCOS, one of the candidate genes causing ovarian failure is the luteinizing hormone (LH) chorionic gonadotropin hormone receptor (LHCGR). Our aim was to study the association of LHCGR polymorphism (rs2293275) with PCOS in our study population.
MATERIALS AND METHODS: Genetic case-control study from multiple gynecological centers from Hyderabad, a cosmopolitan city in South India. The study involved 204 women with PCOS and 204 healthy, sex-, and age-matched controls. Anthropometric and biochemical profiles were taken in a well-designed pro forma. Isolation of deoxyribonucleic acid (DNA) and genotype analysis were done for the entire study population using the polymerase chain reaction-restriction fragment length polymorphism method followed by 12% polyacrylamide gel electrophoresis.
RESULTS: In this study, we have demonstrated an association between LHCGR (rs2293275) polymorphism and PCOS. The frequency of the G allele was 0.60 in PCOS and 0.49 in controls (odds ratio [OR] 1.531, confidence interval [CI] 1.16-2.01, and p-value=0.0026), which indicates that the G allele is associated with PCOS in our population. The GG genotype conferred a significant risk of developing PCOS (OR 3.36, CI 1.96-5.75, and p-value<0.0001). We found a significant association of the GG allele with body-mass index, waist to hip ratio, insulin resistance, LH, and LH/follicle-stimulating hormone (FSH) ratio in PCOS when compared with controls. The AA allele showed high basal FSH levels.
CONCLUSIONS: This study suggests that LHCGR (rs2293275) polymorphism is associated with PCOS and could be used as a relevant molecular marker to identify women with the risk of developing PCOS in our population and may provide an understanding about the etiology of PCOS.

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] Free Access to Full Article 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] Free Access to Full Article 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.

Lenarcik-Kabza A, Łaczmański Ł, Milewicz A, et al.
The influence of endocannabinoid receptor 1 gene variations on anthropometric and metabolic parameters of women with polycystic ovary syndrome.
Endokrynol Pol. 2014; 65(3):181-8 [PubMed] Related Publications
INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with an increasing number of metabolic comorbidities. About 50% of PCOS patients are obese, and insulin resistance affects up to 70% of these women. The endocannabinoid system contributes to human energy homeostasis. CNR1 is a biological candidate for human obesity and related metabolic disorders. The aim of this study was to determine the relationships between CNR1 polymorphisms and anthropometric and metabolic parameters in PCOS women.
MATERIAL AND METHODS: 130 women diagnosed with PCOS according to the Rotterdam criteria were recruited. The control group consisted of 70 healthy women. Medical history was taken, and physical examination as well as assessment of anthropometric (body mass, height, waist and hip circumference, BMI, waist-to-hip ratio [WHR]) and metabolic parameters (glucose and insulin, the insulin resistance index HOMA, lipid profile) was carried out. Genetic studies to detect six CNR1 gene polymorphisms were performed.
RESULTS: The total cholesterol and low-density lipoprotein (LDL) cholesterol levels in PCOS women carrying T/T genotype of rs2023239CNR1 polymorphism were higher than in those with C/T and C/C. There were no statistical differences in other metabolic parameters or in the value of BMI and WHR between the variants of rs2023239 CNR1 polymorphism. The other studied polymorphisms of the CNR1 gene were not associated with anthropometric or metabolic parameters in PCOS women. There were no differences in anthropometric or metabolic parameters between the variants of studied polymorphisms of the CNR1 gene in control women.
CONCLUSIONS: On the basis of our study, it seems that CNR1 polymorphisms are not associated with obesity and metabolic disorders, including insulin resistance, in PCOS women.

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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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.

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