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Carlos Cordon-Cardo

Publications and source records attributed to Carlos Cordon-Cardo.

At least 91 records · Page 5Linked to original sources
PubMed2003

Expression profiling of osteosarcoma cells transfected with MDR1 and NEO genes: regulation of cell adhesion, apoptosis, and tumor suppression-related genes.

The expression patterns of the osteosarcoma cell line U-2 OS, and three derived subclones containing stably transfected MDR1, NEO and MDR1/NEO genes were compared using cDNA microarrays comprising 8976 known genes and expressed sequenced tags. Data provided new insights into three critical issues. First, MDR1 overexpression was associated with altered expression of genes related to several cellular pathways, including (a). drug influx/efflux (eg, dynamin 3), (b). metabolic enzymes (eg, monoamine oxidase A), (c). cell adhesion (eg, EPCAM), (d). apoptotic signaling (eg, I-TRAF), (e). senescence (eg, telomerase RNA binding protein staufen), (f). tumor suppression-related genes (eg, KISS-1 and ephrin B3), and (g). immune system receptors (eg, LENG2). MDR1, EPCAM, and ephrin B3 expression was confirmed by immunohistochemistry. Second, MDR1 transfected cells selected with either doxorubicin or neomycin showed distinct expression profiles that could be related to differential selection. Moreover, hierarchical clustering indicated that cells transfected with MDR1 alone, or cotransfected with NEO, displayed more closely related expression profiles than cells transfected only with NEO. Third, transfection with NEO and selection with neomycin produced a considerable number of expression changes within the cell. This study further elucidates the genetic events associated with MDR1 expression and identifies novel targets associated with multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.

Adolescent↗
PubMed2003

p73alpha regulation by Chk1 in response to DNA damage.

The checkpoint kinase 1 (Chk1) is an essential component of the DNA damage checkpoint. Previous studies have demonstrated an indispensable role for the p53-related transcription factor p73alpha in DNA damage-induced apoptosis. Here, we provide evidence that p73alpha is a target of Chk1. We found that endogenous p73alpha is serine phosphorylated by endogenous Chk1 upon DNA damage, which is a mechanism required for the apoptotic-inducing function of p73alpha. Consistent with this, we discovered that endogenous p73alpha interacts with Chk1 and is phosphorylated by Chk1 at serine 47 in vitro and in vivo. In contrast, Chk2 does not phosphorylate p73alpha in vitro. Moreover, mutation of serine 47 abolishes both Chk1-dependent phosphorylation of p73alpha upon DNA damage in vivo and the ability of Chk1 to upregulate the transactivation capacity of p73alpha. Our data indicate a novel biochemical pathway through which the p73alpha proapoptotic function requires DNA damage-triggered p73alpha phosphorylation by Chk1.

Animals↗
PubMed2003

Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients.

PURPOSE: The purpose is to investigate the clinical relevance of altered patterns of p27 and Skp2 expression in African-American patients with localized prostate cancer. The abundance of p27, an inhibitor of cell proliferation, is controlled by Skp2-dependent proteolysis. EXPERIMENTAL DESIGN: A well-characterized cohort of 162 African-Americans who underwent radical prostatectomy at the Veterans Affairs Medical Center of New York between 1990 and 2000 was studied. We analyzed p27 and Skp2 expression by immunohistochemistry. Altered expression of p27 (defined as <40% tumor cells expressing the protein) and Skp2 (defined as > or ==" BORDER="0">20% tumor cells expressing the protein) were correlated with clinicopathological parameters and time to prostate-specific antigen (PSA) recurrence. RESULTS: Altered expression of p27 and Skp2 was observed in 112 of 162 (69.1%) and 93 of 162 (57.4%) cases, respectively. Inverse patterns of Skp2 and p27 protein expression were seen in 87 of 162 (53.7%) cases. A marginally significant association was found between Skp2 overexpression and extracapsular extension (P = 0.065). Moreover, patients with Skp2 overexpression had a 2.77 years decreased median time to PSA recurrence compared with patients with low Skp2 expression; however, the difference was not statistically significant. In multivariate analysis, only tumor grade and stage independently predicted PSA recurrence in this cohort. CONCLUSIONS: Our data suggest a role for Skp2 overexpression in prostate cancer pathogenesis that might not be exclusively related to p27 degradation. More studies are needed to determine the mechanistic role of Skp2 in prostate cancer.

Black or African American↗
PubMed2002

HDM2 protein overexpression and prognosis in primary malignant melanoma.

Overexpression of the oncogene HDM2 is observed in a substantial proportion of melanomas, including noninvasive and thin lesions, suggesting that HDM2 overexpression may be an early event in melanocyte transformation. To determine the role of HDM2 in the clinical progression of melanoma, we examined whether its expression was associated with patient survival. From November 1972 through November 1982, 134 patients with melanoma who participated in the New York University Melanoma Cooperative Group were studied, if representative tissues and follow-up were available. HDM2 protein expression was assessed immunohistochemically. Unexpectedly, we observed that HDM2 overexpression was statistically significantly associated with improved disease-free survival (relative risk [RR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.89; two-sided chi(2) P =.021) and overall survival (RR = 0.55, 95% CI = 0.33 to 0.94; two-sided chi(2) P =.027) in multivariable analysis. HDM2 overexpression appears to be an independent predictor of survival for patients with primary melanoma; however, larger prospective studies are required for validation.

Female↗
PubMed2002

Separation of live cells in different phases of the cell cycle for gene expression analysis.

BACKGROUND: Homogeneity of cell populations is a basic requirement for gene expression analyses of the cell cycle, such as those based on microarrays. The most common approach to obtain specific populations is the use of synchronization methods that increase the number of cells representing a certain cell cycle stage. On the one hand, conventional synchronization usually causes undesirable effects. On the other hand, cell separation methods may imply loss of RNA quality, another limiting factor for expression profiling. We describe a new strategy to specifically separate live cells in different phases of the cell cycle (G(1) and G(2)/M) to obtain good quality RNA for gene expression analyses. METHODS: The experimental design included sorting G(1) and G(2)/M cells with the vital fluorochrome Hoechst 33342, followed by RNA isolation from the sorted cells. RESULTS: Sorted living G(1) and G(2)/M cells, analyzed by immunocytochemistry and laser scanning cytometry, showed strong enrichment. The quality and specificity of the isolated RNA were demonstrated by northern blot. CONCLUSIONS: This new approach has many potential applications, such as expression profiling of specific cell populations after eliminating the irrelevant data produced by cells in other stages of the cycle.

Benzimidazoles↗
PubMed2002

Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes.

This study was designed to characterize the expression profiles of nine bladder cancer cell lines (T24, J82, 5637, HT1376, RT4, SCaBER, TCCSUP, UMUC-3, and HT1197) using cDNA microarrays (8976 genes and expressed sequence tags). Novel targets involved in bladder cancer progression of potential clinical relevance were validated by immunohistochemistry using tissue microarrays of primary bladder tumors (n = 193 cases). Hierarchical clustering classified uroepithelial cells based on their histopathogenesis and cell cycle alterations. Keratin 10 and caveolin-1 transcripts were more abundant in tumor cells from squamous and invasive origin. Their combined expression was shown to stratify bladder tumors and define squamous differentiation. To assess the robustness of the clustering analysis, a bootstrap resampling technique was used. This grouped tumor cell lines based on their biological properties, including cell cycle and cell adhesion features. E-cadherin, zyxin, and moesin were identified as genes differentially expressed in these clusters and related to the p53, RB, and INK4A status of the cell lines. Loss of these adhesion molecules was associated with stage and grade in primary tumors (P < 0.05), and moesin expression was also associated with survival (P = 0.01). Deregulation of cell cycle and apoptotic pathways, such as mutations or altered expression of p53, pRB, and INK4A (p16), is necessary for uroepithelial transformation. However, it appears that deregulation of cell adhesion is a common event associated with tumor progression in uroepithelial neoplasms.

Biomarkers, Tumor↗
PubMed2002

Evaluation of the proliferation marker MIB-1 in the prognosis of cutaneous malignant melanoma.

BACKGROUND: The proliferation marker MIB-1, which recognizes the Ki-67 antigen, provides independent prognostic information in several tumor types. Its utility in melanoma has been evaluated mostly in studies of thick primary tumors. Its usefulness in thinner lesions has not been assessed adequately. METHODS: A well characterized cohort of 137 patients diagnosed with primary cutaneous melanoma at the New York University School of Medicine between 1972 and 1982 was studied based on the availability of representative tissues and adequate clinical follow-up. Twenty-one tumors were less than or equal to 1.0 mm thick, 94 were between 1.01 and 4.0 mm thick, and 22 were thicker than 4.0 mm. Tumor cell proliferation was assessed by immunohistochemistry using the monoclonal antibody MIB-1. MIB-1 expression was correlated with baseline clinicopathologic parameters, as well as recurrence (RR), disease-free (DFS), and overall survival (OS) rates. Median follow-up among survivors was 6.5 years (range, 5.6-17.5). RESULTS: High proliferative index, defined as 20% or more of tumor cells showing nuclear immunoreactivity, was observed in 65 of 137 (47.4%) cases. High proliferative index was significantly correlated with increased tumor thickness (P < 0.001) and higher stage (P = 0.03). Trends approaching statistical significance were observed with ulceration of the primary tumor (P = 0.09), male gender (P = 0.06), and shorter DFS (P = 0.12). No significant associations were seen between high proliferative index and RR or OS. In multivariate analyses, tumor thickness was the strongest predictor of clinical outcome. CONCLUSIONS: In primary cutaneous melanoma, a high proliferative index is associated with clinicopathologic parameters predictive of worse clinical outcomes. However, it was not an independent predictor of clinical outcome.

Cohort Studies↗
PubMed2002

Alteration of p53 pathway in squamous cell carcinoma of the head and neck: impact on treatment outcome in patients treated with larynx preservation intent.

PURPOSE: To identify the role of p53 pathway alteration(s) as predictors of treatment outcome in patients with advanced, resectable, squamous cell carcinoma (SCC) of the larynx and pharynx treated with larynx preservation (LP) intent. PATIENTS AND METHODS: Seventy-one patients treated on two consecutive LP protocols were studied based on availability of representative tissues. We analyzed the expression pattern of p53, its upstream regulator mdm2, and downstream transcriptional target p21/WAF1 by immunohistochemistry. Positive phenotype was defined as >or= 20% of tumor cells showing nuclear immunoreactivity. Results were correlated with treatment outcomes. RESULTS: Positive phenotype was observed in 35 (49%) of 71 cases for p53, in 52 (74%) of 70 for mdm2, and in 37 (54%) of 68 for p21. There was no correlation between p53 phenotype and p21 nuclear accumulation. The mdm2-negative phenotype was most predictive of major response at the primary tumor site (P =.088). p53-positive phenotype was associated with worse local control with LP (LCLP; 49% v 23%, P =.053) and inferior overall survival (OS; 51% v 29%, P =.017) at 5 years. On Cox regression analysis, p53-positive phenotype predicted inferior OS (P =.033) and showed a trend for worse LCLP (P =.102). When analyzed in a multivariate model as continuous variables, p53 showed a stronger correlation with inferior OS (P <.01), and mdm2 was associated with worse OS (P <.01). CONCLUSION: Among the three markers studied, our data support p53 phenotype as the most informative predictor of unfavorable outcomes in the LP setting, and suggest a role for mdm2 phenotype that requires further exploration. Our analysis does not support a p53-dependent mechanism for p21 expression. Prospective and larger studies are necessary before integration of these molecular markers as part of molecular staging and predictors for organ preservation or other outcomes.

Adult↗
PubMed2002

Adrenocortical carcinoma: clinical, morphologic, and molecular characterization.

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005). The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.

Adolescent↗
PubMed2002

Allotype imbalance or microsatellite mutation in low-grade soft tissue sarcomas of the extremities in adults.

The ability to repair DNA double-strand breaks is essential to maintain chromosomal stability. Virtually all soft tissue sarcomas contain chromosomal instabilities, including clonal aberrations and cytogenetic aberrations. However, the relevance of DNA-dependent protein kinase (DNA-PK) in the pathogenesis of soft tissue sarcoma has not been clarified. The main aim of this work is to compare the prognostic impact of genotypic imbalance in low-grade soft tissue sarcomas of the extremities, and to correlate this with the translational level of DNA-PK. This study investigated 28 adult low-grade malignant spindle cell tumours of the extremities, predominantly fibrosarcomas, for loss of heterozygosity (LOH) and microsatellite mutation on flanking regions of each DNA-PK subunit, with identical immunophenotypes. Twelve different polymorphic markers flanking the specific loci of three subunits comprise the genetic map of DNA-PK, at 22q13, 2q35, and 8q11. Translational activity was also analysed by western blot and conventional immunohistochemistry. The overall sarcoma 5-year survival rate was 61.7%. LOH was identified in the specific coding region of DNA-PK in 39.29% for the DNA-PK catalytic subunit (cs), 17.86% for Ku70, and only 7.14% for Ku80. A positive LOH for DNA-PKcs was shown to be a significant factor for poor survival (log rank test p = 0.0160). Immunoreactivity and immunoblot results correlated with the loss of DNA-PKcs allotype in soft tissue sarcoma (Fisher's exact test p = 0.0037). Ku70 and DNA-PKcs were almost identical in terms of immunoreactivity. In conclusion, whereas microsatellite mutation seems an uncommon event during the evolution of low-grade fibrosarcoma of the extremities in adults, the loss of DNA-PKcs defines a biologically more aggressive subset.

Adolescent↗
PubMed2002

The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147.

Alveolar soft part sarcoma (ASPS) is an unusual tumor of young adults with the characteristic presence on ultrastructural analysis of rhomboid or rectangular cytoplasmic crystals. These membrane-bound crystals are known to form within specific PAS-diastase-resistant electron-dense cytoplasmic granules. The composition of these crystals and the dense granules from which they are derived has remained elusive. After the detection of strong discrete granular cytoplasmic immunoreactivity in ASPS for monocarboxylate transporter 1 (MCT1) in the course of a broad immunohistochemical characterization of an MCT1 antibody, we studied the expression of MCT1 and its interacting partner, CD147, in a panel of 10 ASPS cases using appropriate antibodies. MCT1 is one of a family of widely expressed proton-linked transporters for monocarboxylates such as lactate and pyruvate. In all normal and neoplastic tissues studied to date, MCT1 immunoreactivity is limited to the cell surface. We find that the periodic acid-Schiff-diastase-resistant cytoplasmic granules of ASPS are strongly immunoreactive for MCT1 and CD147. Specifically, intense cytoplasmic granular positivity for MCT1 and CD147 was found in 7 of 10 and 8 of 10 ASPSs, respectively. Ultrastructural immunohistochemistry with immunogold labeling confirmed that the MCT1 immunoreactivity localized to the cytoplasmic electron-dense granules in ASPS. Western blot analysis of several ASPS cases confirmed that the protein reactive with the MCT1 antibody and that reactive with the CD147 antibody both migrated at the size expected for MCT1 and CD147, respectively. Thus, ASPS cells seem to accumulate MCT1-CD147 complexes in the specific cytoplasmic granules known to undergo crystallization. The possible basis for the overproduction or impaired surface localization of these proteins in ASPS remains unclear.

Adult↗
PubMed2002

Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas.

Amplification of the 3q26-q27 has a high prevalence in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. To elucidate its role as a prognostic tool in head and neck squamous cell carcinoma, a yeast artificial chromosome (YAC) contig spanning the entire 3q26-27 region was constructed. The minimal region of amplification was refined within a 1- to 2-Mb genomic segment contained within three overlapping, nonchimeric YAC clones using sequential fluorescent in situ hybridization analysis. These YAC clones containing the apex of amplification were used to develop a two-color fluorescence in situ hybridization assay and applied to the detection of 3q copy numbers in interphase nuclei on archival tumor tissue from 29 cases of normal mucosa, 20 of premalignant mucosa, and 50 of invasive head and neck squamous cell carcinomas. The presence of 3q amplification increased from 3% in normal mucosa to 25% in premalignant mucosa and 56% in invasive cancers (P < 0.01). In invasive tumors, low-level 3q amplification (3 to 4 X copy number) was identified in 18 of 50 primary head and neck cancers and high-level amplification (>4 X copy number) in 10 of 50 cases. With a median follow-up of 82.5 months, an increasing proportion of recurrences (32%, 72%, and 90%; P = 0.003) and cancer-related deaths (14%, 44%, and 70%; P = 0.006) were seen in patients with normal 3q copy number, low-level amplification, and high-level amplification, respectively. The 3-year disease-free (69%, 56%, and 10%; P = 0.001) and cause-specific (94%, 83%, and 40%; P = 0.01) survivals also decreased from normal copy number to low-level and high-level amplification. Only high-level amplification at 3q remained a significant prognostic variable on multivariate analysis including common prognostic predictors for both disease-free (relative risk, 5.1; 95% confidence interval = 1.9 to 13.9) and cause-specific survival (relative risk, 7.6; 95% confidence interval = 1.9 to 29.6). The findings suggest that the 3q copy number status is an important marker for tumor progression and prognostication in patients with head and neck squamous cell carcinoma.

Aged↗
PubMed2002

Clinical significance of molecular expression profiles of Hürthle cell tumors of the thyroid gland analyzed via tissue microarrays.

Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapse-free (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(+/-), cyclin D1(-), and Bcl-2(+/-). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.

Adenoma, Oxyphilic↗
PubMed2002

Loss of p63 expression is associated with tumor progression in bladder cancer.

p63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAp63) or act as a dominant-negative factor toward p53 and p73 (Delta Np63). p63 is expressed in many epithelial compartments and p63(-/-) mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of Delta Np63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.

Animals↗
PubMed2002

The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells.

We utilized gene targeting by homologous recombination to define the role that MEF, a transcriptional activating member of the ETS family of transcription factors, plays in lymphopoiesis. MEF-/- mice have a profound reduction in the number of NK-T and NK cells. Purified MEF-/- NK cells cannot lyse tumor cell targets and secrete only minimal amounts of IFNgamma. Perforin protein expression is severely impaired in MEF-deficient NK cells, likely accounting for the lack of tumor cell cytotoxicity. Promoter studies and chromatin immunoprecipitation analyses demonstrate that MEF and not ETS-1 directly regulates transcription of the perforin gene in NK cells. Our results uncover a specific role of MEF in the development and function of NK cells and in innate immunity.

Animals↗
PubMed2002

Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression.

Ku70 and Ku80 heterodimers function as regulatory subunits of the DNA-dependent protein kinase and play a very important role in the repairing of DNA double-strand breaks. Although Ku70 is proposed as a candidate for a tumor suppressor gene, not many data are available on Ku70 and Ku80 expression in human tumors. The main aim of this study was to investigate the expression of Ku70 and Ku80 in the ultraviolet-induced lesions-nevus cell nevi, lentigos maligna, and malignant melanomas. Nineteen nevus cell nevi, 23 lentigos maligna, 76 primary melanomas, and 31 melanoma metastases were stained immunohistochemically for the presence of Ku70 and Ku80 proteins. Ku70 and Ku80 expression was preserved in about 80% of nevi, 26% of lentigo maligna, 45% of primary melanomas, and 67% of melanoma metastases. Highly significant differences in Ku70 and Ku80 expression were found between nevi, lentigo maligna, and melanomas. In Cox regression, Ku70 and Ku80 were shown to be highly significant influences on patients' prognosis. Significant correlations between Ku70 and Ku80 expressions were found in nevi, lentigo maligna, and primary melanomas. These correlations were not more present in melanoma metastases. To summarize, earlier phases of melanoma progression seem to be connected with the loss of expression of Ku proteins. Metastatic spread is related to dysregulation of the Ku70 and Ku80 axis.

Adult↗