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1.
Gynecol Oncol ; 132(2): 322-7, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24355484

ABSTRACT

OBJECTIVES: Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF). METHODS: FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay. RESULTS: We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased. CONCLUSIONS: Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.


Subject(s)
Carcinoma, Papillary/pathology , Fallopian Tube Neoplasms/pathology , Fallopian Tubes/pathology , Follicular Fluid/chemistry , Ovarian Neoplasms/pathology , Adult , Aged , Carcinogenesis , Cell Line, Tumor , Cell Proliferation , DNA Damage , Epithelium/pathology , Fallopian Tube Neoplasms/genetics , Fallopian Tube Neoplasms/metabolism , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Microarray Analysis , Middle Aged , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Treatment Outcome
2.
Oncogene ; 25(5): 665-76, 2006 Feb 02.
Article in English | MEDLINE | ID: mdl-16247475

ABSTRACT

The cytoskeleton is a dynamic network that undergoes restructuring during various cellular events, influencing cell proliferation, differentiation, and apoptosis. Here, we report that accumulation of c-Jun, a member of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth, dramatically increases upon depolymerization of the cytoskeleton, and that, unexpectedly, this increase is controlled translationally. Depolymerization of the actin or microtubule network induces an increase in c-Jun accumulation with no corresponding increase in c-Jun mRNA or in the half-life of the c-Jun protein, but rather in the translatability of its transcript. This increase is mediated by the untranslated regions (UTRs) of c-Jun mRNA, and is not dependent on activated mitogen-activated protein kinase pathways. This novel mechanism of c-Jun regulation might be relevant to physiological conditions in which c-Jun plays a pivotal role.


Subject(s)
Cytoskeleton/physiology , Protein Biosynthesis/physiology , Proto-Oncogene Proteins c-jun/genetics , Untranslated Regions , Base Sequence , Biopolymers , DNA Primers , HeLa Cells , Humans , MAP Kinase Signaling System , RNA, Messenger/genetics
3.
J Immunol Res ; 2015: 902137, 2015.
Article in English | MEDLINE | ID: mdl-26688824

ABSTRACT

Malignant melanoma is a devastating disease whose incidences are continuously rising. The recently approved antimelanoma therapies carry new hope for metastatic patients for the first time in decades. However, the clinical management of melanoma is severely hampered by the absence of effective screening tools. The expression of the CEACAM1 adhesion molecule on melanoma cells is a strong predictor of poor prognosis. Interestingly, a melanoma-secreted form of CEACAM1 (sCEACAM1) has recently emerged as a potential tumor biomarker. Here we add novel evidences supporting the prognostic role of serum CEACAM1 by using a mice xenograft model of human melanoma and showing a correlation between serum CEACAM1 and tumor burden. Moreover, we demonstrate that serum CEACAM1 is elevated over time in progressive melanoma patients who fail to respond to immunotherapy as opposed to responders and stable disease patients, thus proving a correlation between sCEACAM1, response to treatment, and clinical deterioration.


Subject(s)
Antigens, CD/blood , Cell Adhesion Molecules/blood , Immunotherapy, Adoptive , Melanoma/blood , Melanoma/therapy , Adult , Aged , Animals , Disease Models, Animal , Disease Progression , Female , Humans , Immunotherapy, Adoptive/methods , L-Lactate Dehydrogenase/blood , Longitudinal Studies , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Melanoma/immunology , Melanoma/pathology , Melanoma/surgery , Mice , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Retrospective Studies , Treatment Failure , Treatment Outcome , Tumor Burden , Xenograft Model Antitumor Assays
4.
Oncogene ; 33(35): 4424-32, 2014 Aug 28.
Article in English | MEDLINE | ID: mdl-24077281

ABSTRACT

Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.


Subject(s)
Cystadenocarcinoma, Serous/pathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , MicroRNAs/genetics , Ovarian Neoplasms/pathology , Cell Line, Tumor , Chromosome Deletion , Chromosomes, Human, Pair 6 , Cystadenocarcinoma, Serous/metabolism , Fallopian Tubes/metabolism , Fallopian Tubes/pathology , Female , Forkhead Box Protein O3 , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Signaling System , Ovarian Neoplasms/metabolism
5.
Curr Top Med Chem ; 12(1): 3-10, 2012.
Article in English | MEDLINE | ID: mdl-22196267

ABSTRACT

CEACAM1 adhesion molecule is broadly expressed, participates in pivotal cellular and immunological processes and is involved in cancer. Originally identified as a tumor suppressor, it is now known that in several cancers, including malignant melanoma, CEACAM1 expression correlates with tumor progression and poor survival. Here we review the findings connecting CEACAM1 to malignant melanoma, encompassing in-vitro, in-vivo and patients-derived data. A CEACAM1-mediated mechanism used by melanoma cells to evade immune attack is described in detail. Finally, the potential value of CEACAM1 as a melanoma biomarker and therapeutic target is being discussed.


Subject(s)
Antigens, CD/immunology , Cell Adhesion Molecules/immunology , Melanoma/diagnosis , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Animals , Antigens, CD/blood , Biomarkers, Tumor/blood , Biomarkers, Tumor/immunology , Cell Adhesion Molecules/blood , Humans , Immunotherapy/methods , Melanoma/immunology , Melanoma/therapy , Molecular Targeted Therapy/methods , Skin Neoplasms/immunology
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