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Antonio Giordano

Publications and source records attributed to Antonio Giordano.

At least 19 recordsLinked to original sources
PubMed2026

Epigenetic profiling of circulating cell-free DNA for early detection and minimal residual disease assessment in lung cancer: a focus on DNA methylation.

Lung Cancer (LC) continues to be the biggest cause of cancer-related deaths around the world, mostly because of delayed diagnosis. Even if tissue biopsies and circulating tumor DNA (ctDNA) tests have revolutionized clinical management of LC patients, their effectiveness is restricted in settings with lower tumor burden, molecular heterogeneity, and bias in sampling approaches. In this scenario, the epigenetic profiling of cell-free DNA (cfDNA) stands out as a promising, less invasive approach, accurately detect cancer traces. Evidence from stage I-II disease and CT-detected pulmonary nodules supports the diagnostic potential of cfDNA methylation, although further validation in prospective screening cohorts remains necessary. Beyond genomic alterations, cfDNA epigenetic changes, including DNA methylation, chromatin organization, nucleosome positioning, and fragmentation patterns, reflect multi-dimensional complexity of tumor biology. These properties convey both the functional status and the origin of the circulating DNA fragments, accelerating for tumor integrating genomic analysis. Within this group, DNA methylation is the biologically robust and clinically well-established epigenetic marker, as alterations in methylation linked to cancer often occur in the early stages of tumorigenesis and are commonly found across different cancer cell types. Here, we explored the biological and clinical relevance of the epigenetic landscape of cfDNA in LC patients, particularly focusing on DNA methylation-based biomarkers and their evolving applications towards early diagnosis and post-surgical monitoring of minimal residual disease (MRD). We aimed to comprehensively overview analytical approaches for cfDNA methylation analysis, including targeted and genome-wide profiling strategies, and discuss their integration with machine learning (ML) and multi-omics frameworks in order to improve diagnostic performance and clinical applicability in LC management.

DNA methylation↗
PubMed2024

Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

OBJECTIVE: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFR&#x3b1; is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFR&#x3b1; exposing epitopes that may induce the immune responses to the virus-PDGFR&#x3b1; complex. METHODS: The binding of monomeric human PDGFR&#x3b1; to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFR&#x3b1; locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFR&#x3b1; were evaluated by SPR using SSc monoclonal anti-PDGFR&#x3b1; antibodies and immunoaffinity-purified anti-PDGFR&#x3b1; antibodies from sera of patients with SSc. RESULTS: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P <&#x2009;0.001). In SSc lungs, AAV5 localized&#x2009;in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFR&#x3b1; was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFR&#x3b1; antibodies identified spatially contiguous epitopes derived from PDGFR&#x3b1; and AAV5 that interacted with SSc agonistic antibodies to PDGFR&#x3b1;. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. CONCLUSION: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

Humans↗
PubMed2007

An effective method for adenoviral-mediated delivery of small interfering RNA into mesenchymal stem cells.

Mesenchymal stem cells (MSCs) promise as a main actor of cell-based therapeutic strategies, due to their intrinsic ability to differentiate along different mesenchymal cell lineages, able to repair the diseased or injured tissue in which they are localized. The application of MSCs in therapies requires an in depth knowledge of their biology and of the molecular mechanisms leading to MSC multilineage differentiation. The knockdown of target genes through small interfering RNA (siRNA) carried by adenoviruses (Ad) represents a valid tool for the study of the role of specific molecules in cell biology. Unfortunately, MSCs are poorly transfected by conventional Ad serotype 5 (Ad5) vectors. We set up a method to obtain a very efficient transduction of rat MSCs with low doses of unmodified Ad5, carrying the siRNA targeted against the mRNA coding for Rb2/p130 (Ad-siRNA-Rb2), which plays a fundamental role in cell differentiation. This method allowed a 95% transduction rate of Ad-siRNA in MSC, along with a siRNA-mediated 85% decrease of Rb2/p130 mRNA and a 70% decrease of Rb2/p130 protein 48 h after transduction with 50 multiplicities of infection (MOIs) of Ad5. The effect on Rb2/p130 protein persisted 15 days after transduction. Finally, Ad-siRNA did not compromise the viability of transduced MSCs neither induced any cell cycle modification. The effective Ad-siRNA-Rb2 we constructed, together with the efficient method of delivery in MSCs we set up, will allow an in depth analysis of the role of Rb2/p130 in MSC biology and multilineage differentiation.

Adenoviridae↗
PubMed2007

BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses.

PURPOSE: To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile. EXPERIMENTAL DESIGN: A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the "Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors" at the University of Palermo. Genetic counselling allowed us to recruit a total of 106 unrelated families affected with breast and/or ovarian cancer screened for mutations occurring in the whole BRCA1 gene by automatic direct sequencing. RESULTS: Germline BRCA1 mutations were found in 17 of 106 (16%) Sicilian families. The HBOC profile had a major frequency (66%) of mutations (P < 0.01). A total of 28 sequence variants was identified. Seven of these were pathogenic, 5 unknown biological variant (UV) and 16 polymorphisms. We also identified a pathological mutation (4843delC) as a possible Sicilian founder mutation. CONCLUSIONS: The present study is the first BRCA1 disease-associated mutations analysis in Southern Italian families. The early age of onset of such tumors and the association with the HBOC familial profile could be two valid screening factors for the identification of BRCA1 mutation carriers. Finally, we identified a BRCA1 mutation with a possible founder effect.

Adult↗
PubMed2007

RB and RB2/P130 genes cooperate with extrinsic signals to promote differentiation of rat neural stem cells.

Mechanisms governing commitment and differentiation of the cells of the nervous system begin to be elucidated: how extrinsic and intrinsic components are related remains poorly understood. To investigate this issue, we overexpressed genes of the retinoblastoma (Rb) family RB and RB2/p130, which play an important role during nerve cell maturation, in rat neural stem cells (NSCs). Immunostaining of neurons, astrocytes and oligodendrocytes in cultures overexpressing pRb or pRb2/p130 revealed that these genes affect lineage specification of differentiating NSCs. We observed modifications in percentage of differentiated cells indicating a shift towards the phenotype induced by culture conditions. Results were confirmed by detection of the expression levels of differentiation markers by RT-PCR. Analysis of BrdU incorporation and detection of an early marker of apoptosis suggest that the effect of pRb and pRb2/p130 overexpression is not dependent on the inhibition of cell proliferation, nor does it rely on the regulation of cell survival. Our findings suggest that Rb family genes are involved in fate determination of the cells of the nervous system. However, their role seems subsidiary to that of the extrinsic signals that promote lineage specification and appear to be mediated by a direct effect on the acquisition of a specific phenotype.

Analysis of Variance↗
PubMed2007

Bacterial DNA microarrays for clinical microbiology: the early logarithmic phase.

In this era of coexistence of high-throughput sequencing technologies and serious difficulties in the management of both common and novel infectious syndromes, new techniques which improve the study of micro-organisms is timely. In bacteriology, the most important subjects are bacterial pathogenicity, discovery of the genomic complexity of bacteria, and the epidemiology of antimicrobial resistance traits. From the clinical point of view, genetic testing is flanking phenotypic testing for the assessment of new, difficult to test antibiotic resistance traits, and for correlations with the microbial behaviour in vivo. The demand for faster, comprehensive and highly parallel microbial diagnostics is also cogent even at the basic laboratory level, where the ultimate objective is saving lives. In this setting, DNA microarrays offer a pivotal contribution by allowing performance of hybridization experiments in highly parallel formats, with an increasing reliability. Not only they are useful in deciphering host and microbial pathophysiology, they can also make the difference in the management of prognostic and therapeutic aspects of many diseases. Here, we provide an overview of the current use and the potential of DNA microarrays in clinical bacteriology, and several applications and technical solutions are discussed.

Bacterial Infections↗
PubMed2007

Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer.

Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.

Aged↗
PubMed2007

From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells.

Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.

Bone Marrow Cells↗
PubMed2006

Insulin-like growth factor 1 differentially regulates estrogen receptor-dependent transcription at estrogen response element and AP-1 sites in breast cancer cells.

Cross-talk between insulin-like growth factor 1 (IGF-1) and estrogen receptor alpha (ER) regulates gene expression in breast cancer cells, but the underlying mechanisms remain unclear. Here, we studied how 17-beta-estradiol (E2) and IGF-1 affect ER transcriptional machinery in MCF-7 cells. E2 treatment stimulated ER loading on the estrogen response element (ERE) in the pS2 promoter and on the AP-1 motif in the cyclin D1 promoter. On ERE, similar amounts of liganded ER were found at 1-24-h time points, whereas on AP-1, ER binding fluctuated over time. At 1 h, liganded ER was recruited to ERE together with histone acetyltransferases SRC-1 and p300, ubiquitin ligase E6-AP, histone methyltransferase Carm1 (Carm), and polymerase (pol) II. This coincided with increased histone H3 acetylation and up-regulation of pS2 mRNA levels. At the same time, E2 moderately increased cyclin D1 expression, which was associated with the recruitment of liganded ER, SRC-1, p300, ubiquitin ligase E6-AP (E6L), Mdm2, and pol II, but not other regulatory proteins, to AP-1. In contrast, at 1 h, IGF-1 increased the recruitment of the ER.SRC-1.p300.E6L.Mdm2.Carm.pol II complex on AP-1, but not on ERE, and induced cyclin D1, but not pS2, mRNA expression. Notably, ER knockdown reduced the association of ER, E6L, Mdm2, Carm, and pol II with AP-1 and resulted in down-regulation of cyclin D1 expression. IGF-1 potentiated the effects of E2 on ERE but not to AP-1 and increased E2-dependent pS2, but not cyclin D1, mRNA expression. In conclusion, E2 and IGF-1 differentially regulate ER transcription at ERE and AP-1 sites.

Active Transport, Cell Nucleus↗
PubMed2006

Identification of murine cdk10: association with Ets2 transcription factor and effects on the cell cycle.

Cyclin-dependent kinases (cdks) are the catalytic subunits of a large family of serine/threonine protein kinases whose best-characterized members are key regulators of eukaryotic cell cycle progression. They are activated by binding to regulatory subunits generally termed as cyclins. Cdk10 is a cdc2-related kinase that contains the canonical regulatory Tyr and Thr residues present in all protein kinases and a PSTAIRE-like motif named PISSLRE. Although little is known about this protein, human cdk10 has been shown to encode two different isoforms, each having a distinct function. They differ at both the carboxy- and amino-terminals, although most of the amino acid sequence is predicted to be identical for the two isoforms. A role at the G2/M transition has been suggested for an isoform of cdk10, while the alternative splicing form interacts with the N-terminus of the Ets2 transcription factor. Here we report the cloning and the functional characterization of a cDNA encoding the murine homologue of cdk10. Unlike its human counterpart, only one murine cdk10 protein has been identified, and this unique murine cdk10 cDNA encodes a putative protein of 360 amino acids. Comparison of the amino acid sequences of murine and human cdk10 shows high homology. Murine cdk10 binds Ets2 transcription factors in vitro, does not show a direct involvement in the G2/M transition and, therefore, does not affect the proliferation rate of the cell lines analyzed.

Amino Acid Sequence↗
PubMed2006

Clinical trials.

A clinical trial is a research study in human patients aimed at answering specific health questions. If a clinical trial is well-conducted, it is the fastest way to find treatments that work in people and ways to improve health. A clinical trial is one of the final stages of a long research process. It determines whether new experimental treatments or new ways of using known therapies are safe and effective, but it must meet ethical and scientific quality requirements. This paper reviews the principal phases of clinical trials and discusses the basic requirements needed to ensure a well-conducted experimental study.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

IRS-1-Rad51 nuclear interaction sensitizes JCV T-antigen positive medulloblastoma cells to genotoxic treatment.

The large T-antigen from human polyomavirus JC (JCV T-antigen) is suspected to play a role in malignant transformation. Previously, we reported that JCV T-antigen requires the presence of a functional insulin-like growth factor I receptor (IGF-IR) for transformation of fibroblasts and for survival of medulloblastoma cell lines; that IGF-IR is phosphorylated in medulloblastoma biopsies and that JCV T-antigen inhibits homologous recombination-directed DNA repair, causing accumulation of mutations. Here we are evaluating whether JCV T-antigen positive and negative mouse medulloblastoma cell lines, which significantly differ in their tumorigenic properties, are also different in their abilities to repair double strand breaks of DNA (DSBs). Our results show that despite much stronger tumorigenic potential, JCV T-antigen positive medulloblastoma cells are more sensitive to genotoxic agents (cisplatin and gamma-irradiation). Subsequent analysis of DNA repair of DSBs indicated that homologous recombination-directed DNA repair (HRR) was selectively attenuated in JCV T-antigen positive medulloblastoma cells. JCV T-antigen did not affect HRR directly. In the presence of JCV T-antigen, insulin receptor substrate 1 (IRS-1) translocated to the nucleus where it co-localized with Rad51, possibly attenuating HRR.

Animals↗
PubMed2006

White adipose tissue lacks significant vagal innervation and immunohistochemical evidence of parasympathetic innervation.

Converging evidence indicates that white adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) based on immunohistochemical labeling of a SNS marker (tyrosine hydroxylase [TH]), tract tracing of WAT sympathetic postganglionic innervation, pseudorabies virus (PRV) transneuronal labeling of WAT SNS outflow neurons, and functional evidence from denervation studies. Recently, WAT para-SNS (PSNS) innervation was suggested because local surgical WAT sympathectomy (sparing hypothesized parasympathetic innervation) followed by PRV injection yielded infected cells in the vagal dorsomotor nucleus (DMV), a traditionally-recognized PSNS brain stem site. In addition, local surgical PSNS WAT denervation triggered WAT catabolic responses. We tested histologically whether WAT was parasympathetically innervated by searching for PSNS markers in rat, and normal (C57BL) and obese (ob/ob) mouse WAT. Vesicular acetylcholine transporter, vasoactive intestinal peptide and neuronal nitric oxide synthase immunoreactivities were absent in WAT pads (retroperitoneal, epididymal, inguinal subcutaneous) from all animals. Nearly all nerves innervating WAT vasculature and parenchyma that were labeled with protein gene product 9.5 (PGP9.5; pan-nerve marker) also contained TH, attesting to pervasive SNS innervation. When Siberian hamster inguinal WAT was sympathetically denervated via local injections of catecholaminergic toxin 6-hydroxydopamine (sparing putative parasympathetic nerves), subsequent PRV injection resulted in no central nervous system (CNS) or sympathetic chain infections suggesting no PSNS innervation. By contrast, vehicle-injected WAT subsequently inoculated with PRV had typical CNS/sympathetic chain viral infection patterns. Collectively, these data indicate no parasympathetic nerve markers in WAT of several species, with sparse DMV innervation and question the claim of PSNS WAT innervation as well as its functional significance.

Adipose Tissue, White↗
PubMed2006

How does the human RUNX3 gene induce apoptosis in gastric cancer? Latest data, reflections and reactions.

RUNX3 is the oldest known gene in the RUNX family. Data have demonstrated its function to be thoroughly involved the neurogenesis of the dorsal root ganglia, T-cell differentiation and tumorigenesis of gastric epithelium. As a TGF-beta target, RUNX3 protein is believed to be involved in TGF-beta-mediated tumor suppressor pathway; however, little is known about its role in apoptosis. According to recent data reported by Yamamura et al., (J Biol Chem 2006; 281:5267-76), RUNX3 interacts with FoxO3a/FKHRL1 expressed in gastric cancer cells to activate Bim and induce apoptosis. The cooperation between RUNX3 and the PI3K/Akt signaling pathway component FoxO3a/FKHRL1 suggests the putative role of RUNX3 in the homoeostasis of gastric cells and in stomach cancer control. Here we discuss recent breakthroughs in our understanding of the mechanisms of RUNX3 in gastric malignancy and comment on possible future trends and perspectives.

Animals↗
PubMed2006

Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3beta.

We examined the effects of the adipose hormone leptin on the development of mouse cortical neurons. Treatment of neonatal and adult mice with intraperitoneal leptin (5 mg/kg) induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in pyriform and entorhinal cortex neurons. Stimulation of cultured embryonic cortical neurons with leptin evoked Janus kinase 2 and ERK1/2 phosphorylation and activated the downstream effector 90-kDa ribosomal protein S6 kinase. Moreover, leptin elicited the phosphorylation of the phosphatidylinositol 3-kinase effector Akt and evoked Ser-9 phosphorylation of glycogen synthase kinase-3beta (GSK3beta), an event inactivating this kinase. Leptin-mediated GSK3beta phosphorylation was prevented by the MEK/ERK inhibitor PD98059, the phosphatidylinositol 3-kinase inhibitor LY294002, or the protein kinase C inhibitor GF109203X. Exposure of cortical neurons to leptin also induced Ser-41 phosphorylation of the neuronal growth-associated protein GAP-43, an effect prevented by LY294002 and GF109203X but not by PD98059. Ser-41-GAP-43 phosphorylation is usually high in expanding axonal growth cones. Neurons exposed to 100 ng/ml leptin for 72 h displayed reduced rate of growth cone collapse, a shift of growth cone size distribution toward higher values, and a 4-fold increase in mean growth cone surface area compared with control cultures. The leptin-induced growth cone spreading was hampered in cortical neurons from Lepr(db/db) mice lacking functional leptin receptors; it was associated with localized Ser-9-GSK3beta phosphorylation and mimicked by the GSK3beta inhibitor SB216763. At concentrations preventing GSK3beta phosphorylation, PD98059, LY294002, or GF109203X reversed the leptin-induced growth cone surface enlargement. We concluded that the leptin-mediated regulation of growth cone morphogenesis in cortical neurons relies on upstream regulators of GSK3beta activity.

Animals↗
PubMed2006

pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade.

PURPOSE: Endometrial cancer is the most common gynecologic malignancy. Established prognostic factors are histologic grade, depth of myometrial invasion, and extrauterine spread including retroperitoneal lymph node metastases. Tumorigenesis is a multistep process involving different genetic changes resulting in uncontrolled cellular proliferation, inhibition of apoptosis, and enhanced vascular proliferation among other events. Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is necessary for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. The pathogenesis of the angiogenetic phenotype may involve the inactivation of different tumor suppressor genes. EXPERIMENTAL DESIGN: We investigated the relationship between the expression levels of VEGF and the retinoblastoma family member pRb2/p130 in endometrial carcinoma in relation to histopathologic tumor grade in a cohort of 50 patients. RESULTS: We found that VEGF and pRB2/p130 expression were inversely correlated. Additionally, high grade tumors presented a significantly lower number of cells expressing pRb2/p130 when compared to low grade tumors. A significant positive correlation was found, by means of the Spearman coefficient, between VEGF expression and binary grading (0.450, p-value < 0.005) which is an architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. Additionally, we also found a negative correlation between pRb2/p130 expression levels and binary grading (-0.595, p-value < 0.005). Interestingly, we also found that VEGF and pRb2/p130 expression levels were not related to staging (p-value > 0.005). CONCLUSIONS: These results open up a new perspective including novel markers that, combined together, may be useful in patient screening for endometrial cancer aggressiveness.

Biomarkers, Tumor↗
PubMed2006

JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity.

The progression of cancer is often associated with genomic instability, which may develop as a result of compromised defense mechanisms responsible for the maintenance of chromosomal integrity. These include defects in telomere preservation, chromosomal segregation, and DNA repair. In this review, we discuss molecular interactions between viral and cellular signaling components, which interfere with DNA repair mechanisms, and possibly contribute to the development of a mutagenic phenotype. Our studies indicate that large T-antigen from the human polyomavirus JC (JCV T-antigen) inhibits homologous recombination directed DNA repair (HRR)-causing accumulation of mutations in the affected cells (JCP 2005, in press). Surprisingly, T-antigen does not operate directly, but utilizes insulin receptor substrate 1 (IRS-1), which is the major signaling molecule for insulin-like growth factor I receptor (IGF-IR). Following T-antigen-mediated nuclear translocation, IRS-1 binds Rad51 at the site of damaged DNA. This T-antigen-mediated inhibition of HRR does not function in cells lacking IRS-1, and can be reproduced in the absence of T-antigen by IRS-1 with an artificial nuclear localization signal. The interplay described between the IGF-IR signaling system and JCV T-antigen in the process of DNA repair could be relevant, since nearly 90% of the human population is seropositive for JC virus, JCV T-antigen transforms cells in vitro, is tumorigenic in experimental animals, and the presence of JC virus has been shown in an increasing number of biopsies of human cancer.

Animals↗