An extensive amount of information is currently available to clinical specialists, ranging from details ofclinical symptoms to various types of biochemical data and outputs of imaging devices. Each type of dataprovides information that must be evaluated and assigned to a particular pathology during the diagnosticprocess. To streamline the diagnostic process in daily routine and avoid misdiagnosis, artificial intelligencemethods (especially computer aided diagnosis and artificial neural networks) can be employed. Theseadaptive learning algorithms can handle diverse types of medical data and integrate them into categorizedoutputs. In this paper, we briefly review and discuss the philosophy, capabilities, and limitations of artificialneural networks in medical diagnosis through selected examples
Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.
BACKGROUND. Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS. Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS. The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS. TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013;119:946-54. V C 2012 American Cancer Society.KEYWORDS: TUSC3, methylation, ovarian cancer, glycosylation, progression-free survival, overall survival, biomarker.. INTRODUCTIONEpithelial ovarian cancer is the most lethal gynecologic malignancy and the fourth most frequent cause of cancer-related death among women in industrialized countries. 1 Because >75% of women are diagnosed with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), an early diagnosis presents 1 of the challenges of this disease. Patients with advanced ovarian cancer undergo intensive multimodal therapy consisting of cytoreductive surgery and (neo)adjuvant platinum-based and taxane-based chemotherapy. Regardless of the progress made in surgical and medical therapies over recent decades, the outcome for women with advanced ovarian cancer remains grim. Innovative, hypothesis-driven approaches to biomarker development remain essential even in the era of high-throughput sequencing and various omics. Studies of promoter methylation patterns in tumor suppressor genes have yielded several promising methylated biomarker candidates. [2][3][4] In contrast to a gene or protein expression analysis, methylation can easily be detected using polymerase chain reaction (PCR)-based methods in both tumor material and body fluids. [5][6][7] TUSC3 (tumor suppressor candidate 3), originally named N33, was identified as a potential tumor suppressor gene in prostate cancer 8,9 and is located on chromosome band 8p22. Known homozygous deletions of this region in pancreatic cell lines 10,11 and prostate cancer cell lines 12,13 contain no other cancer-related genes except TUSC3, although mutations of the T...
The role of nonclassical human leukocyte antigens G and E (HLA-G and HLA-E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA-G and HLA-E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA-G and HLA-E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA-G and HLA-E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA-G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA-E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro-host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.
Deregulation of expression and function of cytokines belonging to the transforming growth factor-b (TGF-b) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-b family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-b family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.
Ovarian cancer is one of the most common malignancies in women and contributes greatly to cancer-related deaths. Tumor suppressor candidate 3 (TUSC3) is a putative tumor suppressor gene located at chromosomal region 8p22, which is often lost in epithelial cancers. Epigenetic silencing of TUSC3 has been associated with poor prognosis, and hypermethylation of its promoter provides an independent biomarker of overall and disease-free survival in ovarian cancer patients. TUSC3 is localized to the endoplasmic reticulum in an oligosaccharyl tranferase complex responsible for the N-glycosylation of proteins. However, the precise molecular role of TUSC3 in ovarian cancer remains unclear. In this study, we establish TUSC3 as a novel ovarian cancer tumor suppressor using a xenograft mouse model and demonstrate that loss of TUSC3 alters the molecular response to endoplasmic reticulum stress and induces hallmarks of the epithelial-to-mesenchymal transition in ovarian cancer cells. In summary, we have confirmed the tumor-suppressive function of TUSC3 and identified the possible mechanism driving TUSC3-deficient ovarian cancer cells toward a malignant phenotype.Ovarian cancer (OC) is one of the most common malignancies and the fifth leading cause of cancer-related death in women.1 Despite the recent progress in OC diagnosis and therapy, its overall prognosis remains unfavorable. The heterogeneity of its clinical display reflects the diverse molecular mechanisms contributing to malignant transformation and dissemination of the primary cancer. The tumor suppressor candidate 3 (TUSC3 or N33) gene has been located to chromosomal region 8p22, which is often lost in common epithelial cancers, such as breast, prostate, oral squamous or ovarian cancer. [2][3][4][5][6] According to the Oncomine database, expression of TUSC3 gene is significantly downregulated in OC cases, suggesting the potential clinical relevance of TUSC3 in OC pathogenesis (www.oncomine.org, Supporting Information Fig. 1). Moreover, epigenetic silencing of TUSC3 has been associated with poor prognosis of OC, and hypermethylation of its promoter provides an independent biomarker of overall and disease-free survival in OC patients. 7 Until recently, the molecular function of TUSC3 was inferred from its sequence homology to the yeast protein Ost3p, which forms a subunit of the oligosaccharyltransferase (OST) complex that is responsible for post-and co-translational N-glycosylation of proteins in the endoplasmic reticulum (ER). 8 We demonstrated recently that in embryonic kidney (HEK293) and ovarian cancer cells, TUSC3 localizes to the
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