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1.
Nature ; 582(7810): 95-99, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494066

RESUMO

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.


Assuntos
Carcinogênese/genética , Mutação/genética , Neoplasias/genética , Oncogenes/genética , Animais , Viés , Linhagem da Célula , Classe I de Fosfatidilinositol 3-Quinases/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Humanos , Camundongos , Neoplasias/patologia , Seleção Genética
2.
Anticancer Res ; 40(5): 2667-2673, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366411

RESUMO

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pulmonares/genética , Mutação/genética , Oncogenes , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
DNA Cell Biol ; 39(5): 890-899, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32282228

RESUMO

Lung adenocarcinoma (LUAD) is the most common subtype of nonsmall cell lung cancer, and 5-year survival rate is only 15% in recent years. This study aimed to explore the FAM83A expression and its potential functions in LUAD. Data of LUAD were downloaded from The Cancer Genome Atlas database. Expression level of FAM83A was compared between LUAD samples and adjacent normal samples. The association between FAM83A expression and clinic-pathological parameters was analyzed, as well as copy number variation and methylation status. Kaplan-Meier curve was used to visualize the relationship of FAM83A expression with survival outcomes. Finally, gene set enrichment analysis was used to identify potential signaling pathways in LUAD specimens. FAM83A expression was significantly correlated with four clinical factors in LUAD specimens, age, gender, smoking, and overall survival status (all p < 0.05). High expression level of FAM83A was negatively correlated with methylation level. Moreover, patients in low expression groups exhibited a better prognosis than those in high expressed groups, which was independent of gender (p < 0.001). Histidine metabolism pathway was significantly upregulated in FAM83A-high expressed samples than FAM83A-low expressed samples according to functional enrichment analysis. High expression of FAM83A predicted a poor prognosis in LUAD patients. Our study demonstrated that FAM83A might be a potential biomarker and meaningful therapeutic target in LUAD.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Proteínas de Neoplasias/genética , Oncogenes/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Carcinogênese/genética , Proliferação de Células/genética , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histidina/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
4.
Int J Nanomedicine ; 15: 1693-1708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210560

RESUMO

Introduction: Cancer treatment using functionalized vehicles in order to block involved genes has attracted a remarkable interest. In this study, we investigated the cellular uptake and cytotoxic effects of three sizes of anti Bcl-2 DNAi-conjugated gold nanoparticles by MCF-7 cells. Methods: Three different sizes of gold nanoparticles were synthesized by citrate reduction method and after characterization, the nanoparticles were functionalized by Bcl-2 targeted DNAi. Cell internalization of the nanoparticles was analyzed by atomic absorption spectroscopy and light microscopy. The cytotoxic effects of the nanoparticles were investigated by MTT assay, flow cytometry and RT-PCR of the target gene. Results: While poor cell internalization of bare gold nanoparticles was observed, the results demonstrated that cellular uptake of DNAi-conjugated gold nanoparticles is completely size-dependent, and the largest nanoparticle (~42 nm) revealed the highest internalization rate compared to other sizes (~14 and ~26 nm). Experimental findings showed that the DNAi-conjugated gold nanoparticles induced apoptotic pathway by silencing of the targeted Bcl-2 gene. In addition, supplementary theoretical studies demonstrated that the 42 nm DNAi-conjugated gold nanoparticles have great photothermal conversion efficiency for treatment under external illumination and these nanoparticles can be induced further cytotoxic effect by approximately 10°C temperature elevations. Conclusion: Remarkable photothermal properties of DNAi-conjugated 42 nm Au-NPs in parallel with their high cell internalization and cytotoxic effects introduce them as potential dual functional anticancer nanosystems.


Assuntos
DNA/administração & dosagem , Inativação Gênica , Nanopartículas Metálicas/química , Oncogenes , Proteínas Proto-Oncogênicas c-bcl-2/genética , Apoptose , Linhagem Celular Tumoral , Endocitose , Ouro/química , Humanos , Células MCF-7 , Nanopartículas Metálicas/ultraestrutura , Tamanho da Partícula , Espectrofotometria Ultravioleta , Temperatura
5.
Life Sci ; 250: 117579, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32209425

RESUMO

Although extensive research progress has been made in breast cancer in recent years, yet the morbidity and mortality rates of breast cancer are rising, making it the major disease that endangers women's health. Energy metabolism reprogramming is featured by a state termed "aerobic glycolysis" or the Warburg effect that glycolysis is preferred even under aerobic conditions in neoplastic diseases. Widely acknowledged as an emerging hallmark in cancers, this metabolic switch shows a sophisticated role in the pathogenesis of breast cancer. The regulating effect of non-coding RNAs (ncRNAs) composed of microRNAs, long non-coding RNAs and circular RNAs is closely related to the glycolysis in breast cancer. Therefore, understand the mechanisms of ncRNAs of aerobic glycolysis in breast cancer may provide new strategy for the disease.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicólise , RNA não Traduzido/metabolismo , Aerobiose , Linhagem Celular Tumoral , Feminino , Genes Supressores de Tumor , Glucose/metabolismo , Humanos , MicroRNAs/metabolismo , Neoplasias/metabolismo , Oncogenes , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais
6.
Magy Onkol ; 64(1): 7-11, 2020 Mar 17.
Artigo em Húngaro | MEDLINE | ID: mdl-32181757

RESUMO

Cancer susceptibility but not specific cancer types can be inherited. This susceptibility(ies) is due to inherited germline mutations of key genes of the controllers of genome integrity, translational control, the cell cycle regulation or even the tumor vascularization. Cancer susceptibility can be manifested in various forms of specific syndromes, each associated with different alterations of genes. Most of these genes are tumor suppressors, and the mutations affect one or both alleles. Interestingly, inherited mutations of oncogenes resulting in cancer susceptibility are much rarer, typically affect only one allele, and the inheritance is dominant. However, cancer susceptibility is influenced not only by high penetrance gene defects but also by inherited low penetrance gene mutations, complicating the effective identification of affected individuals and their families.


Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias/genética , Humanos , Oncogenes/genética
7.
Sheng Wu Gong Cheng Xue Bao ; 36(2): 226-240, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32147995

RESUMO

As a member of the histone lysine-specific demethylase family, KDM1A plays a pivotal role in biological processes including signal transduction, chromatin reprogramming, embryo development, hematopoiesis, glucose and lipid metabolism. Recently, increasing studies and clinical evidences suggest that the expression of KDM1A is related to initiation and development of tumors and plays a key role in regulating of initiation and development of tumors, such as prostate cancer, breast cancer, lung cancer and liver cancer. KDM1A binds to distinct complexes and mediates different downstream signaling pathways. However, KDM1A often plays an oncogenic role in the initiation and development of tumors. Based on the current literatures, we describe the latest research of KDM1A in the initiation and progression of various tumors, and summarize its mechanism of actions, to provide clues for cancer therapy.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Histona Desmetilases , Histonas , Humanos , Lisina , Oncogenes
8.
Nat Commun ; 11(1): 732, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024824

RESUMO

Tumors accumulate thousands of mutations, and sequencing them has given rise to methods for finding cancer drivers via mutational recurrence. However, these methods require large cohorts and underperform for low recurrence. Recently, ultra-deep sequencing has enabled accurate measurement of VAFs (variant-allele frequencies) for mutations, allowing the determination of evolutionary trajectories. Here, based solely on the VAF spectrum for an individual sample, we report on a method that identifies drivers and quantifies tumor growth. Drivers introduce perturbations into the spectrum, and our method uses the frequency of hitchhiking mutations preceding a driver to measure this. As validation, we use simulation models and 993 tumors from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium with previously identified drivers. Then we apply our method to an ultra-deep sequenced acute myeloid leukemia (AML) tumor and identify known cancer genes and additional driver candidates. In summary, our framework presents opportunities for personalized driver diagnosis using sequencing data from a single individual.


Assuntos
Genes Supressores de Tumor , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Modelos Genéticos , Mutação , Algoritmos , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Taxa de Mutação , Mutação de Sentido Incorreto , Neoplasias/genética , Neoplasias/patologia , Oncogenes , Medicina de Precisão , Processos Estocásticos
9.
Nat Commun ; 11(1): 1000, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081859

RESUMO

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and they play fundamental roles in immune regulation. Here we introduce an integrated algorithm, ImmLnc, for identifying lncRNA regulators of immune-related pathways. We comprehensively chart the landscape of lncRNA regulation in the immunome across 33 cancer types and show that cancers with similar tissue origin are likely to share lncRNA immune regulators. Moreover, the immune-related lncRNAs are likely to show expression perturbation in cancer and are significantly correlated with immune cell infiltration. ImmLnc can help prioritize cancer-related lncRNAs and further identify three molecular subtypes (proliferative, intermediate, and immunological) of non-small cell lung cancer. These subtypes are characterized by differences in mutation burden, immune cell infiltration, expression of immunomodulatory genes, response to chemotherapy, and prognosis. In summary, the ImmLnc pipeline and the resulting data serve as a valuable resource for understanding lncRNA function and to advance identification of immunotherapy targets.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias/genética , Neoplasias/imunologia , Oncogenes/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Algoritmos , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Bases de Dados Genéticas , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias/classificação
10.
Gene ; 738: 144453, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035242

RESUMO

Breast cancer (BC) is the most common cancer among women that is responsible for the most of the cancer-related death in worldwide. Drug resistance is remaining as a significant clinical obstacle to treat BC patients effectively. Therefore, to help overcome this problem, it is necessary to understand the mechanisms of drug resistance. microRNAs classify as highly conserved non-coding RNAs (~22 nucleotides) and interact with mRNAs-coding genes for direct post-transcriptional repression. It has been reported that miR-21 is overexpressed and also acts as oncomiR in many human malignancies by targeting of several tumor suppressor genes-associated with apoptosis, proliferation and metastasis. Specifically, it has been reported that miR-21 is responsible for the drug resistance and its overexpression is related to the development of Multi Drug Resistance (MDR) in breast cancer. In this review, we discussed about the role of miR-21 on the drug resistance of breast cancer.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Apoptose/genética , Neoplasias da Mama/metabolismo , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Oncogenes/genética , RNA Mensageiro/genética , Transdução de Sinais/genética
11.
Crit Rev Oncol Hematol ; 148: 102894, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062314

RESUMO

Oncogene-driven non small cell lung cancer (NSCLC) is a distinct entity in thoracic oncology. The availability of effective target therapies, like EGFR inhibitors or ALK inhibitors, have revolutionized the prognosis of these patients. However, despite an initial response in the majority of patients, drug resistance ultimately occurs. In some cases, this resistance develops in few clonal cells (oligoprogression), so that a local ablation of these resistant deposits could allow to maintain the same systemic therapy and possibly to prolong patients' survival. For these purposes, stereotactic body radiation therapy (SBRT) is an ideal local ablative treatment, because it is effective, non invasive and with limited side effects. In this review, we aim to analyze available clinical data to verify whether SBRT can allow these patients to continue with existing target therapy longer, delay the switch to other systemic therapies and improve their outcome modifying the natural history of the disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiocirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ablação por Cateter , Progressão da Doença , Humanos , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Oncogenes , Inibidores de Proteínas Quinases , Resultado do Tratamento
12.
Cancer Sci ; 111(4): 1076-1083, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32077199

RESUMO

Rat sarcoma (RAS) is a well-known oncogene that plays important roles in cancer proliferation, cell survival and cell invasion. RAS exists as three major isoforms, Kirsten rat sarcoma (KRAS), Harvey rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS). Mutations of these genes account for approximately 30% of all cancers. Among them, KRAS mutations are the most common, responsible for 85%, followed by NRAS (12%) and HRAS (3%). Although the development of RAS inhibitors has been explored for over the past decade, so far, no effective inhibitor has been found. MicroRNA (miRNA) are a class of small non-coding RNA that control the gene expression of pleural target genes at the post-transcriptional level. MiRNA play critical roles in the physiological and pathological processes at work in cancers, such as cell proliferation, cell death, cell invasion and metastasis. MicroRNA-143 (MIR143) is known to function as a tumor suppressor in a variety of cancers. One of its known mechanisms is suppression of RAS expression and its effector signaling pathways, such as PI3K/AKT and MAPK/ERK. Within the last five years, we developed a potent chemically modified MIR143-3p that enabled us to elucidate the details of the KRAS signaling networks at play in colon and other cancer cells. In this review, we will discuss the role of MIR143-3p in those RAS signaling networks that are related to various biological processes of cancer cells. In addition, we will discuss the possibility of the use of MIR143 as a therapeutic drug for targeting RAS signaling networks.


Assuntos
Antineoplásicos/uso terapêutico , MicroRNAs/genética , Oncogenes/genética , Sarcoma/genética , Proliferação de Células/efeitos dos fármacos , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Membrana/genética , MicroRNAs/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Transdução de Sinais/genética
13.
Adv Exp Med Biol ; 1225: 127-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030652

RESUMO

Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) constitute the human γ-herpesviruses and two of the seven human tumor viruses. In addition to their viral oncogenes that primarily belong to the latent infection programs of these viruses, they encode proteins that condition the microenvironment. Many of these are early lytic gene products and are only expressed in a subset of infected cells of the tumor mass. In this chapter I will describe their function and the evidence that targeting them in addition to the latent oncogenes could be beneficial for the treatment of EBV- and KSHV-associated malignancies.


Assuntos
Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/patogenicidade , Neoplasias/tratamento farmacológico , Neoplasias/virologia , Oncogenes , Microambiente Tumoral , Replicação Viral , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/genética , Herpesvirus Humano 8/efeitos dos fármacos , Herpesvirus Humano 8/genética , Humanos , Oncogenes/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
14.
Nat Commun ; 11(1): 736, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024823

RESUMO

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.


Assuntos
Regulação Neoplásica da Expressão Gênica , Variação Estrutural do Genoma , Neoplasias/genética , Sequências Reguladoras de Ácido Nucleico , Metilação de DNA , Bases de Dados Genéticas , Elementos Facilitadores Genéticos , Genes Supressores de Tumor , Humanos , Oncogenes , Sequenciamento Completo do Genoma
15.
Nature ; 578(7793): 82-93, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025007

RESUMO

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.


Assuntos
Análise Mutacional de DNA , Evolução Molecular , Genoma Humano/genética , Genômica , Mutação , Neoplasias/genética , Proliferação de Células/genética , Senescência Celular/genética , Cromotripsia , Computação em Nuvem , Feminino , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Disseminação de Informação , Masculino , Mutagênese/genética , Neoplasias/classificação , Neoplasias/patologia , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Processamento de RNA/genética , Reprodutibilidade dos Testes , Telomerase/genética , Telômero/genética
16.
17.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553

RESUMO

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
18.
Nat Commun ; 11(1): 69, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900418

RESUMO

Cancer driver gene alterations influence cancer development, occurring in oncogenes, tumor suppressors, and dual role genes. Discovering dual role cancer genes is difficult because of their elusive context-dependent behavior. We define oncogenic mediators as genes controlling biological processes. With them, we classify cancer driver genes, unveiling their roles in cancer mechanisms. To this end, we present Moonlight, a tool that incorporates multiple -omics data to identify critical cancer driver genes. With Moonlight, we analyze 8000+ tumor samples from 18 cancer types, discovering 3310 oncogenic mediators, 151 having dual roles. By incorporating additional data (amplification, mutation, DNA methylation, chromatin accessibility), we reveal 1000+ cancer driver genes, corroborating known molecular mechanisms. Additionally, we confirm critical cancer driver genes by analysing cell-line datasets. We discover inactivation of tumor suppressors in intron regions and that tissue type and subtype indicate dual role status. These findings help explain tumor heterogeneity and could guide therapeutic decisions.


Assuntos
Biologia Computacional/métodos , Genes Supressores de Tumor , Neoplasias/genética , Oncogenes , Metilação de DNA , Humanos , Mutação , Software
19.
Life Sci ; 243: 117230, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923422

RESUMO

AIMS: Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive. MATERIALS AND METHODS: Bioinformatics analysis, CCK-8 assay, Flow cytometry and Western blot were used to analyze gene expression and patient survival, cell proliferation, cell apoptosis and protein level, respectively. KEY FINDINGS: In this study, we comprehensively analyzed the expression profile and prognostic value of HOXC11 in human pan-cancer using online The Cancer Genome Atlas (TCGA) databases. HOXC11 was widely up-regulated in tumor tissues when compared with the normal tissues in pan-cancer across nine cancer types. In addition, high mRNA level of HOXC11 predicted poor overall survival (OS) of patients with adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), mesothelioma (MESO) and pancreatic adenocarcinoma (PAAD), respectively. By comparative analysis, we found that HOXC11 was up-regulated and closely correlated patient OS in COAD and KIRC. Functionally, down-regulation of HOXC11 inhibited cell proliferation but promoted apoptosis of COAD and KIRC in vitro. Mechanistically, HOXC11 promoted cell proliferation of COAD and KIRC might by inactivating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. SIGNIFICANCE: Our findings suggest that HOXC11 may act as a tumor driving gene in COAD and KIRC.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Homeodomínio/fisiologia , Neoplasias Renais/metabolismo , Oncogenes , Adenocarcinoma/patologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/patologia , Regulação para Baixo/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Renais/patologia , PPAR gama/metabolismo , Análise de Sobrevida
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