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Jaume Reventós

Publications and source records attributed to Jaume Reventós.

14 recordsLinked to original sources
PubMed2006

The up-regulation profiles of p21WAF1/CIP1 and RUNX1/AML1 correlate with myometrial infiltration in endometrioid endometrial carcinoma.

We have recently described RUNX1/AML1 up-regulation in endometrioid endometrial carcinoma (EEC), proposing that it could play a role during the initial steps of myometrial infiltration. Some cell cycle regulators, including the cyclin-dependent kinase inhibitor p21WAF1/CIP1, have been described as targets of RUNX1/AML1. In this study, we have attempted to address the question of whether RUNX1/AML1, acting both as a gene transcription activator and a repressor, depending on the context, can be correlated with the expression of p21WAF1/CIP1 in gynecologic malignancies, in particular in EEC, where the role of p21(WAF1/CIP1) remains controversial. Toward this end, we analyzed p21WAF1/CIP1 expression in a large panel of EEC samples using real-time quantitative polymerase chain reaction and tissue microarray immunohistochemistry, and evaluated the extent to which RUNX1/AML1 and p21WAF1/CIP1 interacted in the EEC samples. The strong correlation found between RUNX1/AML1 and p21WAF1/CIP1 suggested cooperation between the 2 genes in EEC, especially in those tumor samples corresponding to stage IC carcinomas, infiltrating more than 50% of the myometrium. We hypothesize that p21WAF1/CIP1 and RUNX1/AML1 interact during the initial steps of tumor dissemination in EEC, and we discuss mechanisms that could underlie myometrial infiltration and/or the promotion of an invasive phenotype.

Biomarkers, Tumor↗
PubMed2006

Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer.

OBJECTIVES: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. METHODS: Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. RESULTS: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. CONCLUSIONS: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.

Aged↗
PubMed2005

Up-regulation of ERM/ETV5 correlates with the degree of myometrial infiltration in endometrioid endometrial carcinoma.

To elucidate alterations in gene expression in endometrioid endometrial carcinoma (EEC), differential gene expression profiling was previously described in both tumour and non-tumour contexts, and the up-regulation of the RUNX1/AML1 proto-oncogene in EEC was characterized. Among the set of genes found to be up-regulated significantly in EEC, the most relevant, ERM/ETV5, corresponds to the PEA3 subfamily and is a member of the Ets family of transcription factors that contain the Ets DNA-binding domain and are involved in matrix remodelling. In the present work, an attempt was made to characterize the expression of ERM/ETV5 in EEC throughout the process of tumourigenesis. Gene expression levels of ERM/ETV5 were quantified by real-time quantitative PCR (RT-Q-PCR) using a large panel of samples ranging from non-invasive IA to metastatic IIIA stages, and protein expression was characterized by tissue array immunohistochemistry (TMA). RT-Q-PCR validated ERM/ETV5 up-regulation in EEC and demonstrated a specific and significant increase restricted to those tumour stages associated with myometrial invasion. TMA showed that ERM/ETV5 up-regulation correlated mainly with the transition from atrophic endometrium to hyperplasia and carcinoma during tumour progression. Furthermore, ERM/ETV5 gene and protein expression levels were associated with low tumour grade. Finally, ERM/ETV5 up-regulation correlated with that of RUNX1/AML1. All of these results lead to the proposal of a co-operative role between ERM/ETV5 and RUNX1/AML1 during the early events of endometrial tumourigenesis, which may be associated with a switch to myometrial infiltration.

Aged↗
PubMed2005

Effect of androgen deprivation therapy in the thyroid function test of patients with prostate cancer.

We have assessed the effect of androgen deprivation therapy (ADT) in the thyroid function test in prostate cancer patients. Serum levels of tri-iodothyronine (T3), thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined in a cross-sectional study that included 279 patients diagnosed with prostate cancer. A subset of 96 patients free of prostate-specific antigen relapse after radical prostatectomy became a control group and 183 patients under continuous ADT formed the study group. Sixty-four patients out of the study group were treated with luteinizing hormone-releasing hormone (LHRH) agonist and 119 with LHRH agonist plus bicalutamide. The average time of ADT was 42.5 months (3-218). Results were as follows. Mean T3 level was 122.7 ng/dl (72.6-213.0) in the control group and 123.8 ng/dl (64.4-228.2) in patients under ADT, p=0.472. Mean T4 level was 7.66 (1.81-4.30) and 7.66 microg/dl (3.60-13.30), respectively, p=0.884. Mean TSH level was 1.58 (0.44-11.70) and 1.81 mU/dl (0.15-6.58), respectively, p=0.007. Mean FT4 level was 1.24 (0.80-1.90) and 1.18 ng/dl (0.80-1.90), respectively, p=0.018. No statistically significant differences between the T3, T4, TSH and FT4 serum levels were detected according to the modality of ADT. The serum level of TSH was higher than 5 mU/l in six patients (2.1%); however, all cases had a normal FT4 serum level. This mild hypothyroidism was detected in two of the 96 patients of the control group (2.1%) and in four of the 183 under ADT (2.2%). Our data show that ADT seems to alter the thyroid function test. A statistically significant increase in TSH serum level and a decrease in FT4 serum level were detected in patients under ADT. However, only a mild hypothyroidism was detected in about 2% of the patients with prostate cancer, independently of ADT.

Aged↗
PubMed2005

PTOV1 enables the nuclear translocation and mitogenic activity of flotillin-1, a major protein of lipid rafts.

PTOV1 is a mitogenic protein that shuttles between the nucleus and the cytoplasm in a cell cycle-dependent manner. It consists of two homologous domains arranged in tandem that constitute a new class of protein modules. We show here that PTOV1 interacts with the lipid raft protein flotillin-1, with which it copurifies in detergent-insoluble floating fractions. Flotillin-1 colocalized with PTOV1 not only at the plasma membrane but, unexpectedly, also in the nucleus, as demonstrated by immunocytochemistry and subcellular fractionation of endogenous and exogenous flotillin-1. Flotillin-1 entered the nucleus concomitant with PTOV1, shortly before the initiation of the S phase. Protein levels of PTOV1 and flotillin-1 oscillated during the cell cycle, with a peak in S. Depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Depletion of either protein markedly inhibited cell proliferation under basal conditions. Overexpression of PTOV1 or flotillin-1 strongly induced proliferation, which required their localization to the nucleus, and was dependent on the reciprocal protein. These observations suggest that PTOV1 assists flotillin-1 in its translocation to the nucleus and that both proteins are required for cell proliferation.

Active Transport, Cell Nucleus↗
PubMed2004

A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma.

Endometrial carcinoma is the most common gynecological malignant disease in industrialized countries. Two clinicopathological types of endometrial carcinoma have been described, based on estrogen relation and grade: endometrioid carcinoma (EEC) and non-EEC (NEEC). Some of the molecular events that occur during the development of endometrial carcinoma have been characterized, showing a dualistic genetic model for EEC and NEEC. However, the molecular bases for endometrial tumorigenesis are not clearly elucidated. In the present work, we attempted to identify new genes that could trigger cell transformation in EEC. We analyzed the differential gene expression profile between tumoral and nontumoral endometrial specimens with cDNA array hybridization. Among the 53 genes for which expression was found to be altered in EEC, the acute myeloid leukemia proto-oncogene, RUNX1/AML1, was one of the most highly up-regulated. The gene expression levels of RUNX1/AML1 were quantified by real-time quantitative PCR, and protein levels were characterized by tissue array immunohistochemistry. Real-time quantitative PCR validated RUNX1/AML1 up-regulation in EEC and demonstrated a specific and significantly stronger up-regulation in those tumor stages associated with myometrial invasion. Furthermore, tissue array immunohistochemistry showed that RUNX1/AML1 up-regulation correlates to the process of tumorigenesis, from normal atrophic endometrium to simple and complex hyperplasia and then, on to carcinoma. These results demonstrate for the first time the up-regulation of RUNX1/AML1 in EEC correlating with the initial steps of myometrial infiltration.

Aged↗
PubMed2003

PTOV-1, a novel protein overexpressed in prostate cancer, shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle.

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.

Adenocarcinoma↗
PubMed2002

Methoxyacetic acid disregulation of androgen receptor and androgen-binding protein expression in adult rat testis.

Chemical agents can disrupt the balance between survival and apoptosis during spermatogenesis and thus give rise to reduced counts of spermatozoa (oligospermia). One such agent that produces significant germ cell apoptosis at specific stages of the cycle of the seminiferous epithelium is methoxy acetic acid (MAA), the active metabolite of a commonly used solvent, methoxyethanol. Although MAA gives rise to apoptosis of pachytene spermatocytes, it is not known whether MAA exerts a direct effect on germ cells or whether it also affects other testicular cell types such as the Sertoli cells. In the present investigation, we tested the hypothesis that MAA has direct effects on Sertoli cells in vivo. In MAA-treated rats, stage-specific expression of androgen receptor (AR) protein in Sertoli cells was significantly altered, as determined by AR immunohistochemistry. In MAA-treated animals, high AR expression was found in Sertoli cells coincident with the MAA-induced apoptosis of late-stage pachytene spermatocytes. The altered expression of AR in MAA-treated animals was also seen in seminiferous tubules harvested by laser capture microdissection. In addition to effects on AR expression, androgen-binding protein (ABP) mRNA levels were also altered in a stage-specific manner. Using a different system for mouse Sertoli cell lines TM4 and MSC-1, positive for either AR or ABP, respectively, we found a direct effect of MAA on ABP protein and mRNA expression in the MSC-1 cell but did not detect an effect on AR protein or mRNA expression in TM4 cells. Mouse fibroblasts that express endogenous AR were stably transfected with two AR promoter/reporter systems (MMTV-CAT and probasin-luciferase, respectively). We used these fibroblasts to examine the ability of MAA to potentiate dihydrotestosterone (DHT) activation of AR. Although MAA did not activate AR directly, it did potentiate DHT activation of the AR by 2- to 4-fold. MAA altered the expression level of AR and ABP in vivo and increased AR transcriptional activity in tissue culture cells. The abnormal spermatogenesis generated by MAA is at least partly due to direct effects on Sertoli cells. It is still unclear whether MAA elicits a proapoptotic signal from Sertoli cells or diminishes a prosurvival signal required by germ cells downstream to altering AR and ABP expression in a stage-specific fashion.

Acetates↗
PubMed2002

Naturally occurring cell death during postnatal development of rat skeletal muscle.

Naturally occurring cell death has been extensively analyzed in many tissues, but little data exist regarding its occurrence in developing skeletal muscle. We investigated its occurrence and time course in rat hindlimb skeletal muscles during the first 3 weeks of postnatal development, its morphological and biochemical features, and the concomitant expression of Bax, Bcl-2, and Bcl-x(L). Myofibers displaying morphological features of apoptosis were found during the first 9 postnatal days. Terminal transferase (TdT)-mediated dUTP-biotinylated nick end labeling (TUNEL)-positive nuclei were present at all days examined and peaked between postnatal days 5 and 7. Total genomic DNA extracted from muscles at postnatal days 5, 7, and 9 showed internucleosomal fragmentation after Southern hybridization. Constitutive levels of Bax, Bcl-2, and Bcl-x(L) were detected by means of reverse transcriptase-polymerase chain reaction (RT-PCR) analysis at all ages examined, with a moderate increase around the period of maximal apoptosis. The results show that apoptosis and a concurrent expression of some genes of the Bcl-2 family, occur postnatally in rat skeletal muscle. This information is relevant to studies addressing the mechanisms of developmental muscle injuries.

Aging↗
PubMed2002

Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells.

BACKGROUND & AIMS: Overexpression of tissue-type plasminogen activator (t-PA) in exocrine pancreatic tumors might be a determinant of the aggressive biological behavior of these tumors. METHODS: Endogenous t-PA production was suppressed by antisense oligonucleotides or transcripts in CAPAN-1 and RWP-1 cell lines. Reciprocally, the t-PA non-expressing BxPC-3 and PANC-1 cells were stably transfected to overexpress t-PA. Recombinant t-PA and chemical inhibitors were also used on these cells. Clones were assayed for invasion and growth in vitro and in vivo. RESULTS: In vitro, specific inhibition of t-PA expression or activity significantly inhibited the proliferation of t-PA-producing RWP-1, CAPAN-1, and SK-PC-1 cells. Antisense constructs were used to generate RWP-1 clones stably suppressed for t-PA expression (AS clones). These clones had a significantly reduced invasion and proliferation on plastic and in soft agar. The addition of recombinant t-PA rescued the growth of the AS clones to parental levels and was mitogenic for other independent pancreas cell lines. This effect did not require plasmin activity. In athymic mice, RWP-1 AS clones produced tumors fivefold smaller than control clones. AS tumors contained a significantly reduced number of Ki67-positive nuclei, fewer mitotic cells, and a remarkably reduced angiogenic network. Finally, the generation of tetracycline-repressed t-PA transfectants in PANC-1 cells confirmed the activity of t-PA in invasion and proliferation in vitro and in vivo. CONCLUSIONS: t-PA, in addition to its known role in invasion, plays other critical roles in pancreas tumor progression, stimulating cancer cell proliferation and tumor-associated angiogenesis.

Animals↗
PubMedDate not supplied

Increased expression of estrogen receptor beta in pachytene spermatocytes after short-term methoxyacetic acid administration.

Degeneration of primary spermatocytes by apoptosis occurs during normal spermatogenesis, as well as in several pathological conditions, including exposure to specific testicular toxicants. The mechanisms that regulate the death and survival of primary spermatocytes, however, are still not well understood. The recent localization of estrogen receptor beta (ERbeta) and P450 aromatase in pachytene spermatocytes suggests a role for estrogens in this step of spermatogenesis. Using a well-known model of pachytene spermatocyte apoptosis in adult rats consisting of the administration of methoxyacetic acid (MAA), we investigated the participation of ERbeta during the initial phase of apoptosis, prior to germ cell loss. Adult rats were treated with a single intraperitoneal dose of MAA, and DNA laddering analysis confirmed apoptotic cell death in the testis. In enriched germ cell fractions and testis from MAA-treated animals, ERbeta mRNA increased significantly at 3 and 6 hours, respectively. Next, stage-specific induction of ERbeta mRNA was demonstrated by use of laser capture microdissection of seminiferous tubules in combination with semiquantitative reverse transcription-polymerase chain reaction. The ERbeta protein also increased significantly after 6 hours and was mainly immunolocalized in the cytoplasm of pachytene spermatocytes of afflicted tubules. The cytoplasmic localization was confirmed by Western blot analysis of isolated cytoplasmic and nuclear fractions of testicular extracts. Finally, the MAA activation of ERbeta was tested in vitro in HepG2 cells cotransfected with ERbeta and a reporter construct that contained a consensus estrogen responsive element. Addition of MAA at similar doses used in vivo elicited a similar estrogenic activation as did estradiol at 1 nmol/L concentration. The present results raise the possibility that cytoplasmic ERbeta participates in the apoptotic process of pachytene spermatocytes induced by MAA. Whether MAA interacts with ERbeta in the cytoplasm of primary spermatocytes, preventing the progression of the first meiotic division, however, remains to be determined.

Acetates↗
PubMedDate not supplied

Ultrastructural changes in prostate cells during hormone-induced canine prostatic hyperplasia.

Benign prostatic hyperplasia is a prevalent disease that has received relatively little attention in spite of its morbidity and remarkable social impact. There are few animal models of prostatic hyperplasia. The dog is the only species, along with humans, in which prostatic hyperplasia develops spontaneously and almost universally with age. The aim of the present study has been to compare the ultrastructural findings in a model of experimentally induced canine prostatic hyperplasia with those of the spontaneously developed changes in untreated dogs. An experimental group of 5 male beagle dogs were castrated and treated with combined steroids (3 weekly doses for over 30 weeks). Prostate samples were surgically obtained every 42 days (experimental stages 0 through 6). The control group consisted of 3 noncastrated dogs that were treated with vehicle and in which samples were taken only at stages 0, 1, 4, and 6. Changes in the control groups were similar but of lower intensity compared to those of the experimental groups. In luminal cells, crowding with papillary projections, prominent, branching microvilli, and abundant, often compartmentalized granules were observed. The most striking change was the previously unreported finding of caveolae in basal cells. They were mostly located in the basal aspect of basal cells and were more prominent in the experimental group and in advanced stages of treatment. These ultrastructural findings have not been previously reported in canine or human prostatic hyperplasia and merit further research. The model of experimentally induced canine prostatic hyperplasia provides an adequate setting for the understanding of this disease.

Androstane-3,17-diol↗