Altered expression of proteins in cancer: function and potential therapeutic targets

Copyright © 2022 Pessoa, Martins, Casimiro, Pérez-Plasencia and Shoshan-Barmatz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The design of innovative cancer treatments requires extensive characterization of the molecular and cellular alterations associated with tumor development and progression. Cancer cells show extensive alterations in protein expression levels, which are drivers of their malignant transformation. Proteins with altered expression levels in cancer are involved in protein synthesis and degradation, signaling and metabolic pathways, DNA repair, apoptosis, and other cellular processes, whose alterations cause tumor development and progression. Characterizing the mechanisms that lead to alterations in protein levels and their cellular effects is an invaluable tool for repurposing those proteins as drug targets. Examples of up-regulated proteins in cancer include the epidermal growth factor receptor 2 (HER2) and the vascular endothelial growth factor (VEGF). HER2 is up-regulated in several cancer types, including breast, gastroesophageal, and non-small-cell lung cancers, making it an effective drug target. VEGF is up-regulated in pancreatic, prostate, and colorectal cancers, among others. Its inhibition is also an effective anticancer treatment, through a decrease in tumor vascularization.These examples demonstrate the modulation of protein levels as an effective anticancer target, which is becoming widely used in patient treatments. These studies also encourage additional research to uncover and test novel up-/down-regulated proteins as potential new therapeutic targets.This work was financed by the European Regional Development Fund (ERDF), through the COMPETE 2020 – Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, under the projects POCI-01-0145-FEDER-028147 (VISCERAL), UIDB/04539/2020, UIDP/04539/2020, and LA/P/0058/2020 (to JP), and PTDC/MED-ONC/28636/2017 (to SC); by Programa de Financiamiento para la Investigación, UNAM, PAPIIT-IN231420, México (to CP-P); and by the National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University, Beer Sheva, Israel (to VS-B).info:eu-repo/semantics/publishedVersio

Genome wide expression analysis in HPV16 Cervical Cancer: identification of altered metabolic pathways

<p>Abstract</p> <p>Background</p> <p>Cervical carcinoma (CC) is a leading cause of death among women worldwide. Human papilloma virus (HPV) is a major etiological factor in CC and HPV 16 is the more frequent viral type present. Our aim was to characterize metabolic pathways altered in HPV 16 tumor samples by means of transcriptome wide analysis and bioinformatics tools for visualizing expression data in the context of KEGG biological pathways.</p> <p>Results</p> <p>We found 2,067 genes significantly up or down-modulated (at least 2-fold) in tumor clinical samples compared to normal tissues, representing ~3.7% of analyzed genes. Cervical carcinoma was associated with an important up-regulation of Wnt signaling pathway, which was validated by in situ hybridization in clinical samples. Other up-regulated pathways were those of calcium signaling and MAPK signaling, as well as cell cycle-related genes. There was down-regulation of focal adhesion, TGF-β signaling, among other metabolic pathways.</p> <p>Conclusion</p> <p>This analysis of HPV 16 tumors transcriptome could be useful for the identification of genes and molecular pathways involved in the pathogenesis of cervical carcinoma. Understanding the possible role of these proteins in the pathogenesis of CC deserves further studies.</p

Editorial: Altered expression of proteins in cancer: function and potential therapeutic targets, volume II

[no abstract available

Characterization of the global profile of genes expressed in cervical epithelium by Serial Analysis of Gene Expression (SAGE)

BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a new technique that allows a detailed and profound quantitative and qualitative knowledge of gene expression profile, without previous knowledge of sequence of analyzed genes. We carried out a modification of SAGE methodology (microSAGE), useful for the analysis of limited quantities of tissue samples, on normal human cervical tissue obtained from a donor without histopathological lesions. Cervical epithelium is constituted mainly by cervical keratinocytes which are the targets of human papilloma virus (HPV), where persistent HPV infection of cervical epithelium is associated with an increase risk for developing cervical carcinomas (CC). RESULTS: We report here a transcriptome analysis of cervical tissue by SAGE, derived from 30,418 sequenced tags that provide a wealth of information about the gene products involved in normal cervical epithelium physiology, as well as genes not previously found in uterine cervix tissue involved in the process of epidermal differentiation. CONCLUSION: This first comprehensive and profound analysis of uterine cervix transcriptome, should be useful for the identification of genes involved in normal cervix uterine function, and candidate genes associated with cervical carcinoma

Diagnóstico clínico y hallazgos necrópsicos en pacientes fallecidos en una unidad de Cuidados Intensivos Pediátricos

Con el fin de identificar la relación entre el diagnóstico clínico antemortem y los hallazgos necrópsicos, se realizó un estudio transversal y descriptivo de 186 historias clínicas de niños fallecidos en la Unidad de Cuidados Intensivos del Hospital Docente Pediátrico del Cerro durante el período comprendido entre junio de 1983 y diciembre del 2002. La tasa de necropsias fue 72.1, alta respecto a otros estudios. Los errores encontrados se clasificaron según los criterios establecidos por Goldman al analizar las discrepancias que pueden ocurrir entre los diagnósticos pre y postmortem de acuerdo con la repercusión vital. Hubo 12 errores tipo I (6.45 %)eigual número de errores tipo II, cifras comparables a lasde otros trabajos. Las enfermedades vinculadas con mayorfrecuencia a errores mayores fueron las infecciones del sistema nervioso central, las neumonías o bronconeumonías, la sepsis, la enfermedad por inclusión citomegálica y el síndrome de Reye. La edad menor de un año y la estadía inferior a 24 horas no determinaron un mayor riesgo de errores I y II. La tasa de necropsias y el porcentaje de errores mayores no sufrieron variaciones significativas en los dos subperíodos analizados. Se concluyó que el análisis de las autopsias constituye un instrumento eficaz para evaluar la calidad asistencial por lo que se insistirá en su realización y estudio periódicos.Palabras Clave: diagnóstico antemortem, diagnóstico postmortem, autopsia, cuidados intensivos.</p

Entamoeba histolytica Up-Regulates MicroRNA-643 to Promote Apoptosis by Targeting XIAP in Human Epithelial Colon Cells

MicroRNAs (miRNAs) are small non-coding RNAs that function as negative regulators of gene expression. Recent evidences suggested that host cells miRNAs are involved in the progression of infectious diseases, but its role in amoebiasis remains largely unknown. Here, we reported an unexplored role for miRNAs of human epithelial colon cells during the apoptosis induced by Entamoeba histolytica. We demonstrated for the first time that SW-480 colon cells change their miRNAs profile in response to parasite exposure. Our data showed that virulent E. histolytica trophozoites induced apoptosis of SW-480 colon cells after 45 min interaction, which was associated to caspases-3 and -9 activation. Comprehensive profiling of 667 miRNAs using Taqman Low-Density Arrays showed that 6 and 15 miRNAs were significantly (FC &gt; 1.5; p &lt; 0.05) modulated in SW-480 cells after 45 and 75 min interaction with parasites, respectively. Remarkably, no significant regulation of the 6-miRNAs signature (miR-526b-5p, miR-150, miR-643, miR-615-5p, miR-525, and miR-409-3p) was found when SW-480 cells were exposed to non-virulent Entamoeba dispar. Moreover, we confirmed that miR-150, miR-643, miR-615-5p, and miR-525 exhibited similar regulation in SW-480 and Caco2 colon cells after 45 min interaction with trophozoites. Exhaustive bioinformatic analysis of the six-miRNAs signature revealed intricate miRNAs-mRNAs co-regulation networks in which the anti-apoptotic XIAP, API5, BCL2, and AKT1 genes were the major targets of the set of six-miRNAs. Of these, we focused in the study of functional relationships between miR-643, upregulated at 45 min interaction, and its predicted target X-linked inhibitor of apoptosis protein (XIAP). Interestingly, interplay of amoeba with SW-480 cells resulted in downregulation of XIAP consistent with apoptosis activation. More importantly, loss of function studies using antagomiRs showed that forced inhibition of miR-643 leads to restoration of XIAP levels and suppression of both apoptosis and caspases-3 and -9 activation. Congruently, mechanistic studies using luciferase reporter assays confirmed that miR-643 exerts a postranscripcional negative regulation of XIAP by targeting its 3′-UTR indicating that it's a downstream effector. In summary, we provide novel lines of evidence suggesting that early-branched eukaryote E. histolytica may promote apoptosis of human colon cells by modulating, in part, the host microRNome which highlight an unexpected role for miRNA-643/XIAP axis in the host cellular response to parasites infection

Gene expression profiles induced by E6 from non-European HPV18 variants reveals a differential activation on cellular processes driving to carcinogenesis

AbstractCervical cancer in developed countries remains as a major concern on public health policies due to incidence and mortality rates. Persistent infection with high risk human papillomavirus is a necessary etiological agent in the progression to invasive cervical carcinoma. A proposed hypothesis is the association between more aggressive HPV variants and the risk to develop cervical cancer. In order to have a global perspective in terms of cellular transcripts and molecular pathways affected by HPV18 E6 intratype variants; we conducted a genome wide analysis of gene expression. Our results show that E6 derived from non-European variants are able to up-regulate cellular transcripts associated to the hallmarks of cancer; such as cell cycle, migration, Wnt pathway and mTor signaling. Moreover, we were able to show that HPV18 E6 from African variant had a major effect on cellular processes such as cell cycle and migration as confirmed by functional studies