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1.
BMC Bioinformatics ; 22(1): 357, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193046

RESUMO

BACKGROUND: An increasing number of studies have shown that lncRNAs are crucial for the control of hormones and the regulation of various physiological processes in the human body, and deletion mutations in RNA are related to many human diseases. LncRNA- disease association prediction is very useful for understanding pathogenesis, diagnosis, and prevention of diseases, and is helpful for labelling relevant biological information. RESULTS: In this manuscript, we propose a computational model named bidirectional generative adversarial network (BiGAN), which consists of an encoder, a generator, and a discriminator to predict new lncRNA-disease associations. We construct features between lncRNA and disease pairs by utilizing the disease semantic similarity, lncRNA sequence similarity, and Gaussian interaction profile kernel similarities of lncRNAs and diseases. The BiGAN maps the latent features of similarity features to predict unverified association between lncRNAs and diseases. The computational results have proved that the BiGAN performs significantly better than other state-of-the-art approaches in cross-validation. We employed the proposed model to predict candidate lncRNAs for renal cancer and colon cancer. The results are promising. Case studies show that almost 70% of lncRNAs in the top 10 prediction lists are verified by recent biological research. CONCLUSION: The experimental results indicated that our proposed model had an accurate predictive ability for the association of lncRNA-disease pairs.


Assuntos
Neoplasias , RNA Longo não Codificante , Algoritmos , Biologia Computacional , Humanos , Neoplasias/genética , RNA Longo não Codificante/genética , Semântica
2.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198826

RESUMO

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which is involved in diverse cellular events in humans. The most well-characterized function of AHR is its ability to upregulate gene transcription after exposure to its ligands, such as environmental toxicants, dietary antioxidants, drugs, and endogenous ligands. The cellular content of AHR is partly controlled by its degradation via the ubiquitin-proteasome system and the lysosome-dependent autophagy. We used human cervical cancer (HeLa) cells to investigate how AHR undergoes protein degradation and how its activity is modulated. Since the glycogen synthase kinase 3 beta (GSK3ß)-mediated phosphorylation can trigger protein degradation and substrates of GSK3ß contain stretches of serine/threonine residues which can be found in AHR, we examined whether degradation and activity of AHR can be controlled by GSK3ß. We observed that AHR undergoes the GSK3ß-dependent, LC3-mediated lysosomal degradation without ligand treatment. The AHR can be phosphorylated in a GSK3ß-dependent manner at three putative sites (S436/S440/S444, S689/S693/T697, and S723/S727/T731), which leads to lysosomal degradation of the AHR protein. Inhibition of the GSK3ß activity suppresses the ligand-activated transcription of an AHR target gene in HeLa, human liver cancer (Hep3B), and human breast cancer (MCF-7) cells. Collectively, our findings support that phosphorylation of AHR by GSK3ß is essential for the optimal activation of its target gene transcription and this phosphorylation may partake as an "off" switch by subjecting the receptor to lysosomal degradation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias/genética , Receptores de Hidrocarboneto Arílico/genética , Transcrição Genética , Autofagia/genética , Células HeLa , Humanos , Lisossomos/genética , Células MCF-7 , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Ubiquitina/genética
3.
Medicina (Kaunas) ; 57(6)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205407

RESUMO

Tumor chemosensitivity assays (TCAs), also known as drug response assays or individualized tumor response tests, have been gaining attention over the past few decades. Although there have been strong positive correlations between the results of these assays and clinical outcomes, they are still not considered routine tests in the care of cancer patients. The correlations between the assays' results (drug sensitivity or resistance) and the clinical evaluations (e.g., response to treatment, progression-free survival) are highly promising. However, there is still a need to design randomized controlled prospective studies to secure the place of these assays in routine use. One of the best ideas to increase the value of these assays could be the combination of the assay results with the omics technologies (e.g., pharmacogenetics that gives an idea of the possible side effects of the drugs). In the near future, the importance of personalized chemotherapy is expected to dictate the use of these omics technologies. The omics relies on the macromolecules (Deoxyribonucleic acid -DNA-, ribonucleic acid -RNA-) and proteins (meaning the structure) while TCAs operate on living cell populations (meaning the function). Therefore, wise combinations of TCAs and omics could be a highly promising novel landscape in the modern care of cancer patients.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética , Estudos Prospectivos
4.
Medicine (Baltimore) ; 100(27): e26535, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232190

RESUMO

BACKGROUND: Accumulating studies have focused on the clinicopathological and prognostic roles of large intergenic noncoding RNA regulator of reprogramming (lincRNA-ROR) in cancer patients. However, the results were controversial and unconvincing. Thus, we performed a meta-analysis to assess the associations between lincRNA-ROR expression and survival and clinicopathological characteristics of cancer patients. METHODS: Hazard ratios for overall survival and disease-free survival with their 95% confidence intervals were used to evaluate the role of lincRNA-ROR expression in the prognosis of cancer patients. Risk ratios with their 95% confidence intervals were applied to assess the relationship between lincRNA-ROR expression and clinicopathological parameters. RESULTS: A total of 18 articles with 1441 patients were enrolled. Our results indicated that high lincRNA-ROR expression was significant associated with tumor size, TNM stage, clinical stage, lymph metastasis, metastasis and vessel invasion of cancer patients. There were no correlations between high lincRNA-ROR expression and age, gender, infiltration depth, differentiation, serum CA19-9 and serum CEA of cancer patients. In addition, high lincRNA-ROR expression was associated with shorter Overall survival and disease-free survival on both univariate and multivariate analyses. Meanwhile, there were no obvious publication bias in our meta-analysis. CONCLUSIONS: LincRNA-ROR expression was associated with the clinicopathological features and outcome of cancer patients, which suggested that lincRNA-ROR might serve as a potential biomarker for cancer prognosis. ETHICAL APPROVAL: Since this study is on the basis of published articles, ethical approval and informed consent of patients are not required.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Humanos , Neoplasias/metabolismo , Prognóstico
6.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204574

RESUMO

Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH, or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.


Assuntos
Éxons , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Precursores de RNA/genética , Splicing de RNA , RNA Mensageiro/genética , Linhagem Celular Tumoral , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Humanos , Modelos Biológicos , Neoplasias/metabolismo , Ligação Proteica , Transporte de RNA , Proteínas de Ligação a RNA/metabolismo
7.
BMC Bioinformatics ; 22(1): 361, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229612

RESUMO

BACKGROUND: Facing the diversity of omics data and the difficulty of selecting one result over all those produced by several methods, consensus strategies have the potential to reconcile multiple inputs and to produce robust results. RESULTS: Here, we introduce ClustOmics, a generic consensus clustering tool that we use in the context of cancer subtyping. ClustOmics relies on a non-relational graph database, which allows for the simultaneous integration of both multiple omics data and results from various clustering methods. This new tool conciliates input clusterings, regardless of their origin, their number, their size or their shape. ClustOmics implements an intuitive and flexible strategy, based upon the idea of evidence accumulation clustering. ClustOmics computes co-occurrences of pairs of samples in input clusters and uses this score as a similarity measure to reorganize data into consensus clusters. CONCLUSION: We applied ClustOmics to multi-omics disease subtyping on real TCGA cancer data from ten different cancer types. We showed that ClustOmics is robust to heterogeneous qualities of input partitions, smoothing and reconciling preliminary predictions into high-quality consensus clusters, both from a computational and a biological point of view. The comparison to a state-of-the-art consensus-based integration tool, COCA, further corroborated this statement. However, the main interest of ClustOmics is not to compete with other tools, but rather to make profit from their various predictions when no gold-standard metric is available to assess their significance. AVAILABILITY: The ClustOmics source code, released under MIT license, and the results obtained on TCGA cancer data are available on GitHub: https://github.com/galadrielbriere/ClustOmics .


Assuntos
Algoritmos , Neoplasias , Análise por Conglomerados , Consenso , Humanos , Neoplasias/genética , Software
8.
Gan To Kagaku Ryoho ; 48(7): 866-872, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34267018

RESUMO

In Japan, 2 comprehensive genome profiling(CGP)tests for cancer was covered by national health insurance in June 2019, and cancer genome medicine was introduced at a total of 225 hospitals designated by the Ministry of Health, Labor and Welfare as"core center hospitals for cancer genome medicine(12 hospitals)"," core hospitals for cancer genome medicine (33 hospitals)", and"collaborative hospitals for cancer genome medicine(180 hospitals)". On the other hand, the interpretation of the results of the cancer CGP test must be discussed by an expert panel conducted at the core center hospitals for cancer genome medicine or the core hospitals for cancer genome medicine, and the results must be explained to patients in order to be covered by insurance. In other words, these hospitals are required to review not only their own cases but also those of collaborating hospitals. In addition, core center hospitals for cancer genome medicine are required to share information and develop human resources with core hospitals and collaborative hospitals for cancer genome medicine. We herein describes the system for providing cancer genome medicine in our hospital as a core center hospital for cancer genome medicine.


Assuntos
Neoplasias , Genômica , Hospitais , Humanos , Japão , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão
9.
Gan To Kagaku Ryoho ; 48(7): 873-877, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34267019

RESUMO

Kyushu University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine since February 2018. Our institution promotes cancer genomic medicine collaborating with 10 Cooperative Hospitals for Cancer Genomic Medicine among Kyushu region. Over 500 solid tumor cases have been examined by cancer genomic profiling tests and the results have been intensively evaluated and discussed in the expert panel meetings. To expand cancer genomic medicine for Kyushu region, we have started a consultation desk for the cancer patients in the local community and began educating programs as cancer genomic medicine seminars for the medical staff of Cooperative Hospitals for Cancer Genomic Medicine. A consultation system has been established to discuss the indication of"Patient requested medical care system". Kyushu University Hospital is now focusing on rare cancer care and medical genetics. Thus close cooperation with cancer genomic medicine and each department has been started. We would like to look back on current progress and issues of cancer genomic medicine in Kyushu University Hospital.


Assuntos
Genômica , Neoplasias , Hospitais Universitários , Humanos , Japão , Neoplasias/genética , Neoplasias/terapia , Encaminhamento e Consulta
10.
Gan To Kagaku Ryoho ; 48(7): 878-881, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34267020

RESUMO

The third-term Basic Plan to Promote Cancer Control Programs in Japan started in 2018. Preparation of the cancer genomic medicine has been newly demanded in this program. Since 2018, the Cancer Genome Medicine Core Base Hospitals( CGM-CBHs), the Cancer Genome Medicine Base Hospitals(CGM-BHs)and the Cancer Genome Medicine Cooperation Hospitals(CGM-CHs)were appointed by the Ministry of Health, Labour and Welfare in Japan. Among these, the CGM-CBHs(including our Tohoku University Hospital)play a key role, and the preparation of the system of the cancer genomic medicine in the district is pushed forward in cooperation with the CGM-BHs and the CGM-CHs. Although the cancer genomic medicine is constantly advancing, a difference in cancer genomic medicine is getting wide between these cancer genomic medicine affiliated hospitals and other medical institutions. Tohoku University Hospital is pushing forward the spread and enlightenment of the cancer genomic medicine in this district as the center in the Tohoku district. Here, we introduce activity in Tohoku University Hospital as a CGM-CBH.


Assuntos
Genômica , Neoplasias , Institutos de Câncer , Hospitais Universitários , Humanos , Japão , Neoplasias/genética , Neoplasias/terapia
11.
Gan To Kagaku Ryoho ; 48(7): 882-886, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34267021

RESUMO

Hokkaido University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine and developed a system to provide cancer genomic medicine in Hokkaido with its liaison hospitals. Since being reimbursed in June 2019, comprehensive cancer genome profiling (CGP) testing showed certain therapeutic efficacy in patients with no standard treatment options, but it also revealed some problems such as the small number of patients who can receive therapeutic drugs matched with gene abnormalities. Since candidate drugs are often unapproved or off-label, it is necessary to smoothly introduce clinical trials, advanced medical treatment system, and patient-proposed health care service. At our hospital, we are focusing on sharing information on clinical trials being conducted in Hokkaido, launching investigator-initiated clinical trials, promoting patient-proposed health care service, promoting a registry study of genetic profiling and targeted therapies in patients with rare cancers and accompanying clinical trials, and incorporating pediatric cancer patients. This paper describes Hokkaido's cancer genomic medicine provision system, including its exit strategy, and the human resource development that serve as its foundation.


Assuntos
Genômica , Neoplasias , Criança , Atenção à Saúde , Hospitais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão
12.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 620-627, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275931

RESUMO

Drug resistance is the main obstacle in the treatment of many cancers. It is of great clinical significance to study the mechanism of drug resistance and find new targets. Multi-omics mainly includes genomics, epigenomics, transcriptomics, proteomics, metabolomics, and radiomics. In recent years, the research of tumor resistance has made rapid development, which has significantly accelerated the discovery of new targets.


Assuntos
Genômica , Neoplasias , Epigenômica , Humanos , Metabolômica , Neoplasias/genética , Proteômica , Tecnologia
13.
Nucleic Acids Res ; 49(W1): W366-W374, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34076240

RESUMO

Advances in DNA sequencing and proteomics mean that researchers must now regularly interrogate thousands of positional gene/protein changes in order to find those relevant for potential clinical application or biological insights. The abundance of already known information on protein interactions, mechanism, and tertiary structure provides the possible means to understand these changes rapidly, though a careful and systematic integration of these diverse datasets is first needed. For this purpose, we developed Mechnetor, a tool that allows users to quickly explore and visualize integrated mechanistic data for proteins or interactions of interest. Central to the system is a careful cataloguing of diverse sources of protein interaction mechanism, and an efficient means to visualize interactions between relevant and/or known protein regions. The result is a finer resolution interaction network that provides more immediate clues as to points of intervention or mechanistic understanding. Users can import protein, interactions, genetic variants or post-translational modifications and see these data in the best known mechanistic context. We demonstrate the tool with topical examples in human genetic diseases and cancer genomics. The tool is freely available at: mechnetor.russelllab.org.


Assuntos
Variação Genética , Mapeamento de Interação de Proteínas , Software , Animais , Doenças Genéticas Inatas/genética , Humanos , Internet , Camundongos , Neoplasias/genética , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Proteínas/genética
14.
J Pathol ; 254(4): 303-306, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097314

RESUMO

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
COVID-19/genética , COVID-19/virologia , Neoplasias/patologia , SARS-CoV-2/patogenicidade , COVID-19/patologia , Genômica/métodos , Humanos , Neoplasias/complicações , Neoplasias/genética , Organoides/patologia , Reino Unido
15.
Nat Commun ; 12(1): 3258, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059679

RESUMO

Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.


Assuntos
Carcinogênese/genética , Macroautofagia/genética , Proteínas de Membrana/genética , Modelos Genéticos , Proteínas Musculares/genética , Neoplasias/genética , Algoritmos , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Simulação por Computador , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Técnicas de Silenciamento de Genes , Glicogênio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/metabolismo , Mutação , Neoplasias/mortalidade , Neoplasias/patologia , Via de Pentose Fosfato/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteoma/genética , RNA-Seq , Análise Serial de Tecidos , Efeito Warburg em Oncologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
BMJ Open ; 11(6): e044543, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083331

RESUMO

INTRODUCTION: Limited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours. METHODS AND ANALYSIS: This is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon's two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT04423185; ChiCTR2000039310.


Assuntos
Neoplasias , Preparações Farmacêuticas , China , Ensaios Clínicos Fase II como Assunto , Genótipo , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão
17.
Mol Cell ; 81(11): 2272-2274, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34087178

RESUMO

Pritykin et al. (2021) establish a comprehensive chromatin atlas of CD8+ T cell dysfunction in chronic viral infection and cancer via analysis of bulk and single-cell ATAC-seq datasets across immune challenges. These results unify the classification scheme and molecular programs driving CD8+ T cell dysfunction across disease settings and will facilitate basic discovery and translational efforts in T cell immunity.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Cromatina , Epigênese Genética , Epigenômica , Humanos , Neoplasias/genética
18.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065345

RESUMO

The P53 pathway is the most important cellular pathway to maintain genomic and cellular integrity, both in embryonic and non-embryonic cells. Stress signals induce its activation, initiating autophagy or cell cycle arrest to enable DNA repair. The persistence of these signals causes either senescence or apoptosis. Over 50% of all solid tumors harbor mutations in TP53 that inactivate the pathway. The remaining cancers are suggested to harbor mutations in genes that regulate the P53 pathway such as its inhibitors Mouse Double Minute 2 and 4 (MDM2 and MDM4, respectively). Many reviews have already been dedicated to P53, MDM2, and MDM4, while this review additionally focuses on the other factors that can deregulate P53 signaling. We discuss that P14ARF (ARF) functions as a negative regulator of MDM2, explaining the frequent loss of ARF detected in cancers. The long non-coding RNA Antisense Non-coding RNA in the INK4 Locus (ANRIL) is encoded on the same locus as ARF, inhibiting ARF expression, thus contributing to the process of tumorigenesis. Mutations in tripartite motif (TRIM) proteins deregulate P53 signaling through their ubiquitin ligase activity. Several microRNAs (miRNAs) inactivate the P53 pathway through inhibition of translation. CCCTC-binding factor (CTCF) maintains an open chromatin structure at the TP53 locus, explaining its inactivation of CTCF during tumorigenesis. P21, a downstream effector of P53, has been found to be deregulated in different tumor types. This review provides a comprehensive overview of these factors that are known to deregulate the P53 pathway in both somatic and embryonic cells, as well as their malignant counterparts (i.e., somatic and germ cell tumors). It provides insights into which aspects still need to be unraveled to grasp their contribution to tumorigenesis, putatively leading to novel targets for effective cancer therapies.


Assuntos
Carcinogênese/genética , Células Germinativas/patologia , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/patologia , Humanos , Neoplasias/genética , Neoplasias/patologia
19.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066490

RESUMO

There is an unmet need for simplified in vitro models of malignancy and metastasis that facilitate fast, affordable and scalable gene and compound analysis. "Adherent" cancer cell lines frequently release "free-floating" cells into suspension that are viable and can reattach. This, in a simplistic way, mimics the metastatic process. We compared the gene expression profiles of naturally co-existing populations of floating and adherent cells in SW620 (colon), C33a (cervix) and HeLa (cervix) cancer cells. We found that 1227, 1367 and 1333 genes were at least 2-fold differentially expressed in the respective cell lines, of which 122 were shared among the three cell lines. As proof of principle, we focused on the anti-metastatic gene NM23-H1, which was downregulated both at the RNA and protein level in the floating cell populations of all three cell lines. Knockdown of NM23-H1 significantly increased the number of floating (and viable) cells, whereas overexpression of NM23-H1 significantly reduced the proportion of floating cells. Other potential regulators of these cellular states were identified through pathway analysis, including hypoxia, mTOR (mechanistic target of rapamycin), cell adhesion and cell polarity signal transduction pathways. Hypoxia, a condition linked to malignancy and metastasis, reduced NM23-H1 expression and significantly increased the number of free-floating cells. Inhibition of mTOR or Rho-associated protein kinase (ROCK) significantly increased cell death specifically in the floating and not the adherent cell population. In conclusion, our study suggests that dynamic subpopulations of free-floating and adherent cells is a useful model to screen and identify genes, drugs and pathways that regulate the process of cancer metastasis, such as cell detachment and anoikis.


Assuntos
Modelos Biológicos , Neoplasias/patologia , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metástase Neoplásica , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Reprodutibilidade dos Testes , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
20.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066883

RESUMO

Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.


Assuntos
Reparo do DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Linhagem Celular Tumoral , Humanos , Reprodutibilidade dos Testes
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