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1.
Am J Pathol ; 193(9): 1298-1318, 2023 09.
Article in English | MEDLINE | ID: mdl-37328102

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.


Subject(s)
Leukemia , Nerve Sheath Neoplasms , Neurofibrosarcoma , Humans , Mice , Animals , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/therapeutic use , Nerve Sheath Neoplasms/drug therapy , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/metabolism , Calmodulin/metabolism , Calmodulin/pharmacology , Calmodulin/therapeutic use , Sirolimus/pharmacology , Cell Proliferation , TOR Serine-Threonine Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Cell Line, Tumor , Mammals/metabolism
2.
Life Sci ; 311(Pt A): 121158, 2022 Dec 15.
Article in English | MEDLINE | ID: mdl-36370870

ABSTRACT

AIMS: Evidence suggests alterations of thyroid hormone levels can disrupt normal bone development. Most data suggest the major targets of thyroid hormones to be the Htra1/Igf1 pathway. Recent discovery by our group suggests involvement of targets WNT pathway, specifically overexpression of antagonist Sfrp4 in the presence of exogenous thyroid hormone. MAIN METHODS: Here we aimed to model these interactions in vitro using primary and isotype cell lines to determine if thyroid hormone drives increased Sfrp4 expression in cells relevant to craniofacial development. Transcriptional profiling, bioinformatics interrogation, protein and function analyses were used. KEY FINDINGS: Affymetrix transcriptional profiling found Sfrp4 overexpression in primary cranial suture derived cells stimulated with thyroxine in vitro. Interrogation of the SFRP4 promoter identified multiple putative binding sites for thyroid hormone receptors. Experimentation with several cell lines demonstrated that thyroxine treatment induced Sfrp4 expression, demonstrating that Sfrp4 mRNA and protein levels are not tightly coupled. Transcriptional and protein analyses demonstrate thyroid hormone receptor binding to the proximal promoter of the target gene Sfrp4 in murine calvarial pre-osteoblasts. Functional analysis after thyroxine hormone stimulation for alkaline phosphatase activity shows that pre-osteoblasts increase alkaline phosphatase activity compared to other cell types, suggesting cell type susceptibility. Finally, we added recombinant SFRP4 to pre-osteoblasts in combination with thyroxine treatment and observed a significant decrease in alkaline phosphatase positivity. SIGNIFICANCE: Taken together, these results suggest SFRP4 may be a key regulatory molecule that prevents thyroxine driven osteogenesis. These data corroborate clinical findings indicating a potential for SFRP4 as a diagnostic or therapeutic target for hyperostotic craniofacial disorders.


Subject(s)
Alkaline Phosphatase , Thyroxine , Mice , Animals , Thyroxine/metabolism , Alkaline Phosphatase/metabolism , Osteoblasts/metabolism , Wnt Signaling Pathway/genetics , Osteogenesis/genetics , Proto-Oncogene Proteins/metabolism
3.
Am J Pathol ; 189(10): 1898-1912, 2019 10.
Article in English | MEDLINE | ID: mdl-31351986

ABSTRACT

It is well established that the epidermal growth factor (EGF) receptor, receptor tyrosine-protein kinase erbB-2 (ERBB2)/human EGF receptor 2 (HER2), and, to a lesser extent, ERBB4/HER4, promote the pathogenesis of many types of human cancers. In contrast, the role that ERBB3/HER3, the fourth member of the ERBB family of receptor tyrosine kinases, plays in these diseases is poorly understood and, until recently, underappreciated. In large part, this was because early structural and functional studies suggested that ERBB3 had little, if any, intrinsic tyrosine kinase activity and, thus, was unlikely to be an important therapeutic target. Since then, however, numerous publications have demonstrated an important role for ERBB3 in carcinogenesis, metastasis, and acquired drug resistance. Furthermore, somatic ERBB3 mutations are frequently encountered in many types of human cancers. Dysregulation of ERBB3 trafficking as well as cooperation with other receptor tyrosine kinases further enhance ERBB3's role in tumorigenesis and drug resistance. As a result of these advances in our understanding of the structure and biochemistry of ERBB3, and a growing focus on the development of precision and combinatorial therapeutic regimens, ERBB3 is increasingly considered to be an important therapeutic target in human cancers. In this review, we discuss the unique structural and functional features of ERBB3 and how this information is being used to develop effective new therapeutic agents that target ERBB3 in human cancers.


Subject(s)
Carcinogenesis/pathology , Neoplasms/pathology , Receptor, ErbB-3/metabolism , Carcinogenesis/metabolism , Humans , Neoplasms/metabolism , Phosphorylation , Signal Transduction
4.
Cell Commun Signal ; 17(1): 74, 2019 07 10.
Article in English | MEDLINE | ID: mdl-31291965

ABSTRACT

BACKGROUND: We have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple erbB receptors with distinct functional characteristics and it is not clear which of these receptors drive MPNST pathogenesis. Here, we test the hypothesis that altered erbB4 expression promotes MPNST pathogenesis by uniquely activating key cytoplasmic signaling cascades. METHODS: ErbB4 expression was assessed using immunohistochemistry, immunocytochemistry, immunoblotting and real-time PCR. To define erbB4 functions, we generated mice that develop MPNSTs with floxed Erbb4 alleles (P0-GGFß3;Trp53+/-;Erbb4flox/flox mice) and ablated Erbb4 in these tumors. MPNST cell proliferation and survival was assessed using 3H-thymidine incorporation, MTT assays, Real-Time Glo and cell count assays. Control and Erbb4-null MPNST cells were orthotopically xenografted in immunodeficient mice and the growth, proliferation (Ki67 labeling), apoptosis (TUNEL labeling) and angiogenesis of these grafts was analyzed. Antibody arrays querying cytoplasmic kinases were used to identify erbB4-responsive kinases. Pharmacologic or genetic inhibition was used to identify erbB4-responsive kinases that drive proliferation. RESULTS: Aberrant erbB4 expression was evident in 25/30 surgically resected human MPNSTs and in MPNSTs from genetically engineered mouse models (P0-GGFß3 and P0-GGFß3;Trp53+/- mice); multiple erbB4 splice variants that differ in their ability to activate PI3 kinase and nuclear signaling were present in MPNST-derived cell lines. Erbb4-null MPNST cells demonstrated decreased proliferation and survival and altered morphology relative to non-ablated controls. Orthotopic allografts of Erbb4-null cells were significantly smaller than controls, with reduced proliferation, survival and vascularization. ERBB4 knockdown in human MPNST cells similarly inhibited DNA synthesis and viability. Although we have previously shown that broad-spectrum erbB inhibitors inhibit Ras activation, Erbb4 ablation did not affect Ras activation, suggesting that erbB4 drives neoplasia via non-Ras dependent pathways. An analysis of 43 candidate kinases identified multiple NRG1ß-responsive and erbB4-dependent signaling cascades including the PI3K, WNK1, STAT3, STAT5 and phospholipase-Cγ pathways. Although WNK1 inhibition did not alter proliferation, inhibition of STAT3, STAT5 and phospholipase-Cγ markedly reduced proliferation. CONCLUSIONS: ErbB4 promotes MPNST growth by activating key non-Ras dependent signaling cascades including the STAT3, STAT5 and phospholipase-Cγ pathways. ErbB4 and its effector pathways are thus potentially useful therapeutic targets in MPNSTs.


Subject(s)
Nerve Sheath Neoplasms/pathology , Receptor, ErbB-4/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic , Gene Expression Regulation, Neoplastic , Humans , Mice , Phospholipase C gamma/metabolism , Phosphorylation , Receptor, ErbB-4/genetics , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction , ras Proteins/metabolism
5.
Calcif Tissue Int ; 101(3): 300-311, 2017 09.
Article in English | MEDLINE | ID: mdl-28391432

ABSTRACT

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.


Subject(s)
Prenatal Exposure Delayed Effects/pathology , Skull Base/drug effects , Skull Base/growth & development , Thyroxine/toxicity , Animals , Female , Male , Mice , Mice, Inbred C57BL , Pregnancy , Thyroid Hormones/toxicity , X-Ray Microtomography
6.
PLoS One ; 11(12): e0167805, 2016.
Article in English | MEDLINE | ID: mdl-27959899

ABSTRACT

Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.


Subject(s)
Cranial Sutures/drug effects , Prenatal Exposure Delayed Effects/pathology , Thyroxine/adverse effects , Animals , Female , High-Temperature Requirement A Serine Peptidase 1 , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Inbred C57BL , Pregnancy , Prenatal Exposure Delayed Effects/diagnostic imaging , Prenatal Exposure Delayed Effects/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Wnt Signaling Pathway/genetics
7.
Birth Defects Res A Clin Mol Teratol ; 106(10): 803-813, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27435288

ABSTRACT

BACKGROUND: Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis. METHODS: Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/-. RESULTS: By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/- model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/- phenotype was significantly different from the wild-type control. Twist 1 +/- cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression. CONCLUSION: Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/- model. These results highlight difficultly in experimentally modeling gene-environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803-813, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Abnormalities, Drug-Induced , Craniosynostoses , Gene-Environment Interaction , Nuclear Proteins/genetics , Phenotype , Thyroxine/adverse effects , Twist-Related Protein 1/genetics , Abnormalities, Drug-Induced/genetics , Abnormalities, Drug-Induced/metabolism , Abnormalities, Drug-Induced/pathology , Animals , Craniosynostoses/chemically induced , Craniosynostoses/genetics , Craniosynostoses/metabolism , Craniosynostoses/pathology , Disease Models, Animal , Gene Expression Regulation , Mice , Mice, Mutant Strains , Osteogenesis/drug effects , Osteogenesis/genetics , Thyroxine/pharmacology
8.
J Immunol ; 195(4): 1676-84, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26179905

ABSTRACT

HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A-C (encoded by FCGR3A and FCGR2A-C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell-mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1-infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1-infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2C(bright)NKG2A(-)CD57(+)FcRγ(-)), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell-Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.


Subject(s)
Herpes Simplex/immunology , Herpesvirus 1, Human/immunology , Immunoglobulin G/immunology , Killer Cells, Natural/immunology , Animals , Antibody-Dependent Cell Cytotoxicity/genetics , Antibody-Dependent Cell Cytotoxicity/immunology , Cell Degranulation/genetics , Cell Degranulation/immunology , Cell Line , Disease Susceptibility , Epistasis, Genetic , Gene Expression , Genetic Variation , Genotype , Herpes Simplex/genetics , Humans , Immunoglobulin G/genetics , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Immunoglobulin kappa-Chains/genetics , Immunoglobulin kappa-Chains/immunology , Immunophenotyping , Phenotype , Polymorphism, Genetic , Receptors, IgG/genetics , Receptors, IgG/metabolism , Virus Activation/immunology
9.
Neuro Oncol ; 17(5): 678-84, 2015 May.
Article in English | MEDLINE | ID: mdl-25326496

ABSTRACT

BACKGROUND: Immunoglobulin γ marker (GM) and κ marker (KM) allotypes, hereditary antigenic determinants of γ and κ chains, respectively, have been shown to be associated with immunity to a variety of self and nonself antigens, but their possible contribution to immunity to the tumor-associated antigens epidermal growth factor receptor (EGFR) and EGFR variant (v)III has not been evaluated. The aim of the present investigation was to determine whether the interindividual variation in endogenous antibody responsiveness to EGFR and EGFRvIII is associated with particular GM, KM, and Fcγ receptor (FcγR) genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma. METHODS: A total of 126 Caucasian participants with glioblastoma were genotyped for several GM, KM, and FcγR alleles and characterized for IgG antibodies to EGFR and EGFRvIII antigens. RESULTS: The anti-EGFR antibody levels associated with GM 3/3 homozygotes and GM 3/17 heterozygotes were similar (15.9 vs 16.4 arbitrary units [AU]/µL) and significantly lower than those associated with GM 17/17 homozygotes (19.6 AU/µL; nominal P = .007). Participants homozygous for the GM 21 allele also had significantly higher levels of anti-EGFR antibodies than GM 5/5 homozygotes and GM 5/21 heterozygotes (20.1 vs 16.0 and 16.3 AU/µL; nominal P = .005). Similar associations were found with immune responsiveness to EGFRvIII. Higher anti-EGFR and anti-EGFRvIII antibody levels were associated with enhanced overall survival (16 vs 11 mo, nominal P = .038 and 20 vs 11 mo, nominal P = .004, respectively). CONCLUSIONS: GM allotypes contribute to humoral immunity to EGFR in glioblastoma.


Subject(s)
ErbB Receptors/immunology , Glioblastoma/genetics , Glioblastoma/immunology , Immunoglobulin Gm Allotypes/genetics , Immunoglobulin Gm Allotypes/immunology , Immunoglobulin Km Allotypes/genetics , Immunoglobulin Km Allotypes/immunology , Adolescent , Adult , Aged , Female , Genotype , Glioblastoma/mortality , Humans , Male , Middle Aged , Receptors, IgG/genetics , Survival , Young Adult
10.
J Infect Dis ; 210(11): 1823-6, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-24973460

ABSTRACT

Human cytomegalovirus (HCMV) is a risk factor for many human diseases, but among exposed individuals, not everyone is equally likely to develop HCMV-spurred diseases, implying the presence of host genetic factors that might modulate immunity to this virus. Here, we show that antibody responsiveness to HCMV glycoprotein B (gB) is significantly associated with particular immunoglobulin GM (γ marker) genotypes. Anti-HCMV gB antibody levels were highest in GM 17/17 homozygotes, intermediate in GM 3/17 heterozygotes, and lowest in GM 3/3 homozygotes (28.2, 19.0, and 8.1 µg/mL, respectively; P=.014). These findings provide mechanistic insights in the etiopathogenesis of HCMV-spurred diseases.


Subject(s)
Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Genes, Immunoglobulin , Immunity, Humoral , Viral Envelope Proteins/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Case-Control Studies , Genotype , Humans , Immunoglobulin Allotypes/genetics , Immunoglobulin Allotypes/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology
11.
Immunobiology ; 219(2): 113-7, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24054945

ABSTRACT

Immunoglobulin κ constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (κ marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25-30% of breast cancer patients and is associated with poor prognosis. Using a matched case-control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (γ marker) and Fcγ receptor (FcγR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR=1.77, CI 1.06-2.95). Additionally, KM genotypes-individually and in particular epistatic combinations with FcγRIIa genotypes-contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/immunology , Carcinoma/diagnosis , Carcinoma/immunology , Immunoglobulin kappa-Chains/genetics , Receptors, IgG/genetics , Alleles , Antigens, Neoplasm/immunology , Brazil , Case-Control Studies , Female , Follow-Up Studies , Genetic Association Studies , Genotype , Humans , Immunity, Humoral , Japan , Linkage Disequilibrium , Polymorphism, Genetic , Prognosis , Receptor, ErbB-2/immunology , Risk Factors
12.
Hum Immunol ; 74(12): 1656-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23994584

ABSTRACT

GM and KM allotypes-hereditary antigenic variants of immunoglobulin γ and κ chains, respectively-and the genetic variants of activating Fcγ receptors (FcγR) are associated with the immunobiology of several malignant diseases, but their role in susceptibility to prostate cancer has not been examined. This investigation aimed to determine whether these genes-individually or in particular epistatic combinations-contribute to the risk of prostate cancer. We genotyped DNA from 200 Caucasian patients with prostate cancer and 185 healthy controls (matched for age, race, gender, and geography) for several GM, KM, FcγRIIa, and FcγRIIIa alleles by molecular methods. None of the genotypes by itself was associated with the risk of prostate cancer. However, particular alleles at GM 23 and FcγRIIa loci interactively contributed to the risk of this malignancy (p = 0.031), the odds ratios ranging from 0.44 in subjects homozygous for the GM 23- allele at the IgG2 locus and for the histidine allele at the FcγRIIa locus to 2.86 in subjects homozygous for the GM 23+ allele at the IgG2 locus and the histidine allele at the FcγRIIa locus. To our knowledge, this is the first report implicating GM and FcγR loci as risk/protective factors for prostate cancer. Additional, independent, studies are warranted to confirm and extend these findings.


Subject(s)
Epistasis, Genetic , Genetic Loci , Immunoglobulin Fc Fragments/genetics , Immunoglobulin G/genetics , Prostatic Neoplasms/genetics , Receptors, IgG/genetics , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , Immunoglobulin Gm Allotypes/genetics , Immunoglobulin Km Allotypes/genetics , Male , Middle Aged , Neoplasm Grading , Odds Ratio , Prostatic Neoplasms/pathology
13.
Hum Immunol ; 73(11): 1155-8, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22884983

ABSTRACT

Immunoglobulin GM allotypes, antigenic determinants of γ chains, are encoded by three very closely linked codominant genes on chromosome 14q32. Particular GM alleles/haplotypes are associated with antibody responses to certain tumor antigens and contribute to the cytotoxicity of breast cancer cells, but their possible role in susceptibility to this malignancy has not been adequately examined. Using a matched case-control design, we genotyped a large (1710 subjects) study population from Japan and Brazil for several GM alleles to determine whether these determinants are associated with susceptibility to breast cancer. After adjusting for the potential confounders, the GM 3 allele of IgG1 was significantly associated with susceptibility to breast cancer in white subjects from Brazil (OR=2.07, CI 1.16-3.71; p=0.0147). These data show that Caucasians with the GM 3 allele are over twice as likely to develop breast cancer as those who lack this allele. Since this allele modulates an immune evasion strategy of cytomegalovirus, the results also shed light on the possible mechanism underlying the reported involvement of this virus in the etiology of breast cancer.


Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease , Immunoglobulin G/genetics , Breast Neoplasms/immunology , Case-Control Studies , Female , Genetic Markers , Genotype , Humans , Immunoglobulin G/immunology , Population Groups/genetics , Receptors, IgG/genetics
14.
Circ Cardiovasc Genet ; 4(6): 605-13, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22010139

ABSTRACT

BACKGROUND: Increasing evidence points to a direct role for altered microRNA (miRNA or miR) expression levels in cardiovascular remodeling and disease progression. Although alterations in miR expression levels have been directly linked to cardiac hypertrophy, fibrosis, and remodeling, their role in regulating gene expression during thoracic aortic aneurysm (TAA) development has yet to be explored. METHODS AND RESULTS: The present study examined miR expression levels in aortic tissue specimens collected from patients with ascending TAAs by quantitative real-time PCR, and observed decreased miR expression (miRs -1, -21, -29a, -133a, and -486) as compared with normal aortic specimens. A significant relationship between miR expression levels (miRs -1, -21, -29a, and -133a) and aortic diameter was identified; as aortic diameter increased, miR expression decreased. Through the use of a bioinformatics approach, members of the matrix metalloproteinase (MMP) family, proteins involved in TAA development, were examined for putative miR binding sites. MMP-2 and MMP-9 were identified as potential targets for miR-29a and miR-133a, respectively, and MMP-2 was subsequently verified as a miR-29a target in vitro. A significant inverse relationship between miR-29a and total MMP-2 was then identified in the clinical TAA specimens. CONCLUSIONS: These findings demonstrate altered miR expression patterns in clinical TAA specimens, suggesting that the loss of specific miR expression may allow for the elaboration of specific MMPs capable of driving aortic remodeling during TAA development. Importantly, these data suggest that these miRs have biological and clinical relevance to the behavior of TAAs and may provide significant targets for therapeutic and diagnostic applications.


Subject(s)
Aorta, Thoracic/metabolism , Aortic Aneurysm, Thoracic/genetics , Down-Regulation , Matrix Metalloproteinase 2/metabolism , MicroRNAs/genetics , Aged , Aorta, Thoracic/growth & development , Aortic Aneurysm, Thoracic/enzymology , Aortic Aneurysm, Thoracic/metabolism , Female , Humans , Male , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , MicroRNAs/metabolism , Middle Aged , Organ Size
15.
Am J Physiol Heart Circ Physiol ; 301(4): H1656-66, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21666120

ABSTRACT

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP(+/-)), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1-MMP(+/-) compared with WT. LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT post-MI and was higher in the MT1-MMP(+/-) mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP(+/-) group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP(+/-) group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP(+/-) group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process.


Subject(s)
Heart/physiology , Matrix Metalloproteinase 14/physiology , Myocardial Infarction/enzymology , Ventricular Remodeling/physiology , Animals , Collagen/metabolism , Immunohistochemistry , Kaplan-Meier Estimate , Latent TGF-beta Binding Proteins/metabolism , Matrix Metalloproteinase 14/biosynthesis , Matrix Metalloproteinase 14/genetics , Mice , Mice, Knockout , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Smad2 Protein/biosynthesis , Smad2 Protein/genetics , Survival , Ventricular Function, Left/physiology
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