Although Epidermal Growth Factor Receptor (EGFR) overexpression is observed frequently in hepatocellular carcinomas (HCC), specific gene deregulation mechanisms remain unknown. Our aim was to investigate the prognostic significance of the combined protein and gene/chromosome 7 numerical alterations. Using tissue microarray technology, thirty-five (n = 35) paraffin embedded histologically confirmed HCCs were cored and re-embedded in a paraffin block. Immunohistochemistry was performed for the determination of EGFR protein levels and evaluated by the performance of digital image analysis. Chromogenic in situ hybridization was also performed based on the use of EGFR gene and chromosome 7 centromeric probes, respectively. EGFR overexpression was observed in 26/35 (74.2%) cases and was correlated to the grade of the tumors and also to the history of the patients (p = 0.013, p = 0.036, respectively). Numerical alterations regarding gene and chromosome 7 were identified in 4/35 (11.4%) and 12/35 (43.2%) cases associated to the grade of the tumors (p = 0.019, p = 0.001, respectively) and to the survival rate of the patients (p = 0.037, p = 0.001, respectively). EGFR overall expression was also correlated to the gene copies (p = 0.020). EGFR gene numerical alterations -although rare- and also chromosome 7 aneuploidy maybe affect prognosis in HCC patients. To our knowledge this is the first chromogenic in situ hybridization analysis based on tissue microarrays in hepatocellular carcinoma.
Among intra-cellular homeostasis mechanisms, ubiquitination plays a critical role in protein metabolism regulation by degrading proteins via activating a broad spectrum of ubiquitin chains. In fact, ubiquitination and sumoylation signaling pathways are characterized by increased complexity regarding the molecules and their interactions. The Ubiquitin-Proteasome System (Ub-PS) recognizes and targets a broad spectrum of protein substrates. Ubiquitin conjugation modifies each substrate protein determining its biochemical fate (degradation). A major functional activity of Ub-PS is autophagy mechanism regulation. Interestingly, Ub-PS promotesall stages of bulk autophagy (initiation, execution, and termination). Autophagy is a crucial catabolic process that provides protein degradation and for this reason the interaction with Ub-PS is crucial. Furthermore, ubiquitination controls and regulates specific types of protein targets. Ub-PS is also involved in oxidative cellular stress and DNA damage response. Additionally, the functional role of Ub-PS in ribosome machinery regulation seems to be crucial. Concerning carcinogenesis, Ub-PS is involved in malignant disease development and progression by negatively affecting the corresponding TGF-B-, MEEK/MAPK/ERK-JNK- dependent signaling pathways. In the current review article, we describe the role of Ub-PSbiochemicalmodifications and alterations in oral squamous cell carcinoma (OSCC).
Aim: Topoisomerases represent a class of nucleic enzymes involved in the DNA replication, transcription and also chromosome topological formation. Topoisomerase IIa (Topo Iia – gene location 17q21) inhibition promotes cell death and for this reason, it is a target for specific chemotherapy (anthracyclines, podophyllotoxines). Our aim was to investigate the potential prognostic significance of its protein expression in squamous cell carcinomas of the tongue (TSCCs) based on a quantitative, digital image analysis method. Materials and methods: We analysed immunohistochemically eighty‐seven (n = 87) archival, primary TSCCs using a monoclonal anti‐Topo IIa antibody. A computerised image analysis assay was applied for the evaluation of the results [nuclear labelling index (NLI)]. Survival analysis was also performed. Results: Topo IIa protein was overexpressed in 48/87 (55.1%) cases. High NLI values were detected in 17/48 (35.4%), whereas moderate levels of expression were detected in 31/48 (64.6%) cases. Statistical significance was not assessed correlating overall protein expression to grade or stage of the examined tumours (P = 0.88, P = 0.73, respectively), but only to the anatomical region (P = 0.04). Cox regression analysis showed that Topo IIa and also the size of the tumours were strongly associated to the survival of the patients (P = 0.01, P = 0.02, respectively). Conclusions: Topo IIa protein overexpression is a frequent event in TSCCs. Topo IIa may be used as a prognostic factor and also as a basis for targeted chemotherapy strategies in TSCCs. Furthermore, digital image analysis improves the quantification of immunohistochemical stains in an accurate and fast way.
DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule’s structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.
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