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1.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202589

RESUMO

BACKGROUND: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. METHODS: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. RESULTS: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. CONCLUSION: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.


Assuntos
Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Purinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Proteínas Supressoras de Tumor/metabolismo
2.
FASEB J ; 35(8): e21681, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34196428

RESUMO

The sodium/iodide symporter (NIS) expresses at the basolateral plasma membrane of the thyroid follicular cell and mediates iodide accumulation required for normal thyroid hormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidism due to impaired iodide accumulation in thyroid follicular cells underscoring the significance of NIS for thyroid physiology. Here we report novel findings derived from the thorough characterization of the nonsense NIS mutant p.R636* NIS-leading to a truncated protein missing the last eight amino acids-identified in twins with congenital hypothyroidism. R636* NIS is severely mislocalized into intracellular vesicular compartments due to the lack of a conserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS is barely targeted to the plasma membrane and therefore iodide transport is reduced. Deletion of the PDZ-binding motif causes NIS accumulation into late endosomes and lysosomes. Using PDZ domain arrays, we revealed that the PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by a PDZ-PDZ interaction. Furthermore, in CRISPR/Cas9-based SCRIB deficient cells, NIS expression at the basolateral plasma membrane is compromised, leading to NIS localization into intracellular vesicular compartments. We conclude that the PDZ-binding motif is a plasma membrane retention signal that participates in the polarized expression of NIS by selectively interacting with the PDZ-domain containing protein SCRIB, thus retaining the transporter at the basolateral plasma membrane. Our data provide insights into the molecular mechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the thyroid cancer field considering the relevance of NIS-mediated radioactive iodide therapy for differentiated thyroid carcinoma.


Assuntos
Proteínas de Membrana/metabolismo , Simportadores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Membrana Celular/metabolismo , Códon sem Sentido , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/metabolismo , Sequência Conservada , Cães , Endossomos/metabolismo , Células HEK293 , Humanos , Lisossomos/metabolismo , Células Madin Darby de Rim Canino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Domínios PDZ/genética , Estrutura Secundária de Proteína , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Simportadores/química , Simportadores/genética , Glândula Tireoide/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética
3.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072831

RESUMO

Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of ß-catenin was reversed by proteasome inhibitor via the ß-catenin/ GSK3ß signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the ß-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/tratamento farmacológico , Histona Desacetilases/genética , Proteínas Repressoras/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , beta Catenina/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Repressoras/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Temozolomida/efeitos adversos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Artigo em Inglês | MEDLINE | ID: mdl-34071861

RESUMO

High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer with highly metastatic properties. A small non-coding RNA, microRNA (miRNA) was discovered to be a major regulator in many types of cancers through binding at the 3'-untranslated region (3'UTR), leading to degradation of the mRNA. In this study, we sought to investigate the underlying mechanisms involved in the dysregulation of miR-200c-3p in HGSC progression and metastasis. We identified the upregulation of miR-200c-3p expression in different stages of HGSC clinical samples and the downregulation of the tumor suppressor gene, Deleted in Liver Cancer 1 (DLC1), expression. Over expression of miR-200c-3p in HGSC cell lines downregulated DLC1 but upregulated the epithelial marker, E-cadherin (CDH1). Based on in silico analysis, two putative binding sites were found within the 3'UTR of DLC1, and we confirmed the direct binding of miR-200c-3p to the target binding motif at position 1488-1495 bp of 3'UTR of DLC1 by luciferase reporter assay in a SKOV3 cell line co-transfected with vectors and miR-200c-3p mimic. These data showed that miR-200c-3p regulated the progression of HGSC by regulating DLC1 expression post-transcription and can be considered as a promising target for therapeutic purposes.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Ovarianas/genética , Proteínas Supressoras de Tumor/genética
5.
Medicine (Baltimore) ; 100(22): e26219, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087900

RESUMO

BACKGROUND: Autophagy is closely related to skin cutaneous melanoma (SKCM), but the mechanism involved is unclear. Therefore, exploration of the role of autophagy-related genes (ARGs) in SKCM is necessary. MATERIALS AND METHODS: Differential expression autophagy-related genes (DEARGs) were first analysed. Univariate and multivariate Cox regression analyses were used to evaluate the expression of DEARGs and prognosis of SKCM. Further, the expression levels of prognosis-related DEARGs were verified by immunohistochemical (IHC) staining. Finally, gene set enrichment analysis (GSEA) was used to explore the underlying molecular mechanisms of SKCM. RESULTS: Five ARGs (APOL1, BIRC5, EGFR, TP63, and SPNS1) were positively correlated with the prognosis of SKCM. IHC verified the results of the differential expression of these 5 ARGs in the bioinformatics analysis. According to the receiver operating characteristic curve, the signature had a good performance at predicting overall survival in SKCM. The signature could classify SKCM patients into high-risk or low-risk groups according to distinct overall survival. The nomogram confirmed that the risk score has a particularly large impact on the prognosis of SKCM. Calibration plot displayed excellent agreement between nomogram predictions and actual observations. Principal component analysis indicated that patients in the high-risk group could be distinguished from those in low-risk group. Results of GSEA indicated that the low-risk group is enriched with aggressiveness-related pathways such as phosphatidylinositol-3-kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. CONCLUSION: Our study identified a 5-gene signature. It revealed the mechanisms of autophagy that lead to the progression of SKCM and established a prognostic nomogram that can predict overall survival of patients with SKCM. The findings of this study provide novel insights into the relationship between ARGs and prognosis of SKCM.


Assuntos
Autofagia/genética , Biologia Computacional/métodos , Melanoma/genética , Neoplasias Cutâneas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína L1/genética , Receptores ErbB/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Proteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nomogramas , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Fatores de Risco , Survivina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
6.
Nat Commun ; 12(1): 3646, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131137

RESUMO

U5 snRNP is a complex particle essential for RNA splicing. U5 snRNPs undergo intricate biogenesis that ensures that only a fully mature particle assembles into a splicing competent U4/U6•U5 tri-snRNP and enters the splicing reaction. During splicing, U5 snRNP is substantially rearranged and leaves as a U5/PRPF19 post-splicing particle, which requires re-generation before the next round of splicing. Here, we show that a previously uncharacterized protein TSSC4 is a component of U5 snRNP that promotes tri-snRNP formation. We provide evidence that TSSC4 associates with U5 snRNP chaperones, U5 snRNP and the U5/PRPF19 particle. Specifically, TSSC4 interacts with U5-specific proteins PRPF8, EFTUD2 and SNRNP200. We also identified TSSC4 domains critical for the interaction with U5 snRNP and the PRPF19 complex, as well as for TSSC4 function in tri-snRNP assembly. TSSC4 emerges as a specific chaperone that acts in U5 snRNP de novo biogenesis as well as post-splicing recycling.


Assuntos
Ribonucleoproteína Nuclear Pequena U5/química , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Spliceossomos/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Regulação para Baixo , Células HeLa , Humanos , Proteínas Nucleares/metabolismo , Fatores de Alongamento de Peptídeos , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Splicing de RNA , Fatores de Processamento de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Recombinantes de Fusão , Ribonucleoproteínas Nucleares Pequenas/química , Fatores de Transcrição , Proteínas Supressoras de Tumor/genética
7.
Aging (Albany NY) ; 13(11): 15269-15284, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074803

RESUMO

Rho-related BTB domain (RhoBTB) proteins belong to Rho guanosine triphosphatases (GTPases). Their putative role implicated in carcinogenesis has been supported by accumulating evidence. However, their expression pattern and potential role in acute myeloid leukemia (AML) remain unclear. We profiled RHOBTB mRNA expression via the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Survival analysis was conducted with GEPIA2 and UALCAN. Univariate and multivariate Cox regression analyses were performed to validate RHOBTB genes as independent prognostic indicators in the LAML cohort from The Cancer Genome Atlas (TCGA). Data regarding expression in different subtypes and relationships with common disease-related genes were retrieved from UALCAN. Co-expressed genes were screened out and subsequently subjected to functional enrichment analysis. We observed aberrant transcription levels of RHOBTB genes in AML patients. RHOBTB2 was identified as a prognostic candidate for overall survival (OS), independent of prognosis-related clinical factors and genetic abnormalities. Moreover, RHOBTB2 expression was increased in non-acute promyelocytic leukemia (APL) subtypes, patients without FLT3 mutation and PML/RAR fusion, and imparted a positive correlation with the expression of FLT3, FHL1, and RUNXs. Co-expressed genes of RHOBTB2 were enriched in functional pathways in AML. Our findings suggest that RHOBTB2 might be a novel biomarker and independent prognostic indicator in AML and provide insights into the leukemogenesis and molecular network of AML.


Assuntos
Proteínas de Ligação ao GTP/genética , Leucemia Mieloide Aguda/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Ligação ao GTP/metabolismo , Regulação Leucêmica da Expressão Gênica , Humanos , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/metabolismo
8.
Mol Cell ; 81(13): 2765-2777.e6, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102105

RESUMO

The BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages. Targeting BRCA1-BARD1 to DSB-proximal sites requires BARD1-mediated nucleosome interaction and histone mark recognition. Here, we report the cryo-EM structure of BARD1 bound to a ubiquitinated nucleosome core particle (NCPUb) at 3.1 Å resolution and illustrate how BARD1 simultaneously recognizes the DNA damage-induced mark H2AK15ub and DNA replication-associated mark H4K20me0 on the nucleosome. In vitro and in vivo analyses reveal that the BARD1-NCPUb complex is stabilized by BARD1-nucleosome interaction, BARD1-ubiquitin interaction, and BARD1 ARD domain-BARD1 BRCT domain interaction, and abrogating these interactions is detrimental to HR activity. We further identify multiple disease-causing BARD1 mutations that disrupt BARD1-NCPUb interactions and hence impair HR. Together, this study elucidates the mechanism of BRCA1-BARD1 complex recruitment and retention by DSB-flanking nucleosomes and sheds important light on cancer therapeutic avenues.


Assuntos
Proteína BRCA1/química , Histonas/química , Complexos Multiproteicos/química , Nucleossomos/química , Proteínas Supressoras de Tumor/química , Ubiquitina-Proteína Ligases/química , Proteínas de Xenopus/química , Animais , Proteína BRCA1/genética , Histonas/genética , Humanos , Modelos Moleculares , Complexos Multiproteicos/genética , Mutação , Nucleossomos/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Proteínas de Xenopus/genética , Xenopus laevis
9.
Arkh Patol ; 83(3): 45-51, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34041896

RESUMO

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.


Assuntos
Síndrome de Birt-Hogg-Dubé , Neoplasias Renais , Neoplasias Cutâneas , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Humanos , Proteínas Proto-Oncogênicas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética
10.
Biomed Res Int ; 2021: 9951405, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997050

RESUMO

Although colorectal cancer (CRC) is common, there is a paucity of information regarding its molecular pathogenesis. Studies have shown that miRNAs play pivotal roles in the development and progression of CRC. There is a need to further investigate the biological functions of miRNAs in CRC. In particular, it has been reported that miR-942-5p exhibits tumor-suppressive properties. Thus, we analyzed the functional significance of miR-942-5p in CRC and the underlying molecular mechanisms. We found that miR-942-5p was downregulated in CRC tissues and cells. Cell Counting Kit-8, EdU, and colony formation assays revealed that the overexpression of miR-942-5p by mimics inhibited the proliferation of CRC cells. Use of the miR-942-5p inhibitor effectively enhanced the proliferative potential of CRC cells. Further, in vivo xenograft experiments confirmed these results. Increased expression of miR-942-5p suppressed the invasion, migration, and epithelial-mesenchymal transition of CRC cell lines, while decreased miR-942-5p expression had the opposite effect. CCBE1, a secretory molecule for lymphangiogenesis, was established as a downstream target of miR-942-5p, and its expression was inversely correlated with the expression of miR-942-5p in CRC cells. Additionally, cotransfection of the miR-942-5p inhibitor with si-CCBE1 into CRC cells reversed the effects induced by miR-942-5p overexpression. In conclusion, we confirmed that miR-942-5p exerts oncogenic actions in CRC by targeting CCBE1 and identified miR-942-5p as a potential clinical biomarker for CRC diagnosis and therapy.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais , Transição Epitelial-Mesenquimal/genética , MicroRNAs , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Xenoenxertos , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteínas Supressoras de Tumor/genética
11.
Anticancer Res ; 41(5): 2583-2589, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952487

RESUMO

BACKGROUND/AIM: High-grade gliomas have a poor prognosis despite standard treatment. The aim of the study was to identify new prognostic factors to select patients who need more intense treatment. PATIENTS AND METHODS: Forty-three consecutive patients underwent surgery plus chemoradiotherapy for pathologically diagnosed high-grade gliomas (grade III, IV). RESULTS: The median survival time was 989 days, and the 1-year survival rate was 87.6%. Among patients with grade IV disease, the median survival time, 1-year, and 2-year survival rate were 814 days, 82.6%, and 58.7%, respectively. In the univariate analysis, unmethylated MGMT promoter (p=0.0495), brainstem infiltration (p=0.0004), basal ganglia as the primary lesion site (p=0.0056), 3-dimensional conformal radiotherapy (p=0.0286), and <50 Gy (p=0.0049) were associated with a poor prognosis. In the multivariate analysis, only brainstem infiltration retained significance (HR for death, 0.21; 95% CI=0.06-0.70; p=0.011). CONCLUSION: Brainstem infiltration is a novel prognostic factor for poor prognosis in patients with high-grade gliomas.


Assuntos
Tronco Encefálico/imunologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/tratamento farmacológico , Glioma/radioterapia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gânglios da Base/imunologia , Gânglios da Base/patologia , Tronco Encefálico/patologia , Quimiorradioterapia/efeitos adversos , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Glioma/imunologia , Glioma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Regiões Promotoras Genéticas/genética
12.
Mol Cell ; 81(13): 2736-2751.e8, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932349

RESUMO

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Ácido Mevalônico/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Camundongos , Camundongos Transgênicos , Proteínas Supressoras de Tumor/genética
13.
Lung Cancer ; 157: 30-39, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34052706

RESUMO

OBJECTIVES: We aimed to explore the feasibility of 2D and 3D radiomics signature based on the unenhanced computed tomography (CT) images to predict BRCA1-associated protein 1 (BAP1) gene mutation status for malignant pleural mesothelioma (MPM) patients. MATERIALS AND METHODS: 74 patients with MPM were retrospectively enrolled (22 mutant BAP1, 52 wild-type BAP1 demonstrated by Sanger sequencing). The radiomic features were extracted respectively from the 2D and 3D segmentation of unenhanced pre-treatment CT images, and the dataset was randomly divided into training (n = 51) and test (n = 23) sets for radiomics model development and internal validation. The synthetic minority over-sampling technique (SMOTE) was used for data balancing in the training set. 2D or 3D features were sequentially selected by ICC > 0.8, correlation analysis (cut-value 0.7), univariate analysis or univariate logistic regression (LR), which were involved into multivariate LR for LR model construction. Following the comparison of the 2D and 3D models by the ROC analysis and Delong test for AUC, the calibration and clinical utility of 2D and 3D models were evaluated. RESULTS: 3D radiomic features showed better ICCs compared with 2D in both intra- (P < 0.001) and inter-observer (P < 0.001) analysis. 3D radiomic model based on selected features developed from a balanced training dataset presented a favorable predictive performance with AUC of 0.786 and 0.768 in the training and test sets, respectively. The predictive performance of 3D model was superior to 2D model (1 feature) both in the training (AUC 0.786 vs. 0.683, P = 0.036) and the test (AUC 0.768 vs.0.652, P = 0.441) set. The calibration curve and decision curves also indicate a better BAP1 prediction performance and clinical benefit for 3D model than that of 2D model. CONCLUSION: The developed unenhanced CT-based 3D radiomics signature is potential as a noninvasive marker for predicting BAP1 mutation status.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Mutação , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
14.
Cancer Sci ; 112(7): 2884-2894, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934428

RESUMO

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene.


Assuntos
Neoplasias Colorretais/enzimologia , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Factuais , Progressão da Doença , Ativação Enzimática , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfopiruvato Hidratase/antagonistas & inibidores , Fosfopiruvato Hidratase/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Interferência de RNA , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Vemurafenib/farmacologia
15.
Mol Cell ; 81(11): 2332-2348.e9, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33974912

RESUMO

Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.


Assuntos
Carcinogênese/genética , DNA Helicases/genética , Proteínas Intrinsicamente Desordenadas/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Cromatina/patologia , DNA Helicases/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Mapeamento de Interação de Proteínas , Estabilidade Proteica , Transporte Proteico , Transdução de Sinais , Análise de Sobrevida , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
16.
Science ; 372(6543)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33986153

RESUMO

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.


Assuntos
Processamento Alternativo , Neoplasias da Mama/patologia , Metástase Neoplásica/genética , RNA/genética , RNA/metabolismo , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Algoritmos , Animais , Sítios de Ligação , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Progressão da Doença , Éxons , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Transplante de Neoplasias , Conformação de Ácido Nucleico , Plectina/genética , Ligação Proteica , Interferência de RNA , RNA Nuclear Pequeno/química , RNA Nuclear Pequeno/metabolismo , RNA-Seq , Ribonucleoproteína Nuclear Pequena U2/genética , Software , Spliceossomos/metabolismo , Proteínas Supressoras de Tumor/genética
17.
Mol Cell ; 81(7): 1367-1369, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798413

RESUMO

Mutations in ataxia telangiectasia mutated (ATM) kinase lead to cerebellar neurodegeneration. In this issue of Molecular Cell, Lee et al. (2021) revealed how transcription-induced reactive oxygen species and DNA-RNA hybrids activate PARP enzymes, generating the nucleic acid poly-ADP-ribose, which promotes the accumulation of protein aggregates in A-T-like disorders.


Assuntos
Ataxia Telangiectasia , Ácidos Nucleicos , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Poli(ADP-Ribose) Polimerase-1 , Poli ADP Ribosilação , Poli(ADP-Ribose) Polimerases/metabolismo , Agregados Proteicos , Proteostase , Proteínas Supressoras de Tumor/genética
18.
Arch Virol ; 166(6): 1643-1651, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33796885

RESUMO

The Ras association domain family 1 isoform A (RASSF1A), cytotoxic T lymphocyte antigen 4 (CTLA-4), and signal transducer and activator of transcription 4 (STAT4) genes play a role in regulating the cell cycle, apoptosis, and the autoimmune response against cancer. We investigated the genotype frequency and the possible association of the rs2073498 (RASSF1A), rs5742909 (CTLA-4) and rs7574865 (STAT4) genetic variants with hepatitis C virus (HCV)-G4-mediated hepatocellular carcinoma (HCC) progression in Egyptian patients. Fifty patients with HCV infection, 50 patients with HCV-mediated HCC, and 50 age- and sex-matched healthy controls were recruited. The investigated variants were genotyped based on polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The Ser133 mutant G4 variant of the rs2073498 SNP in RASSF1A exhibited a positive correlation with HCC incidence risk (OR = 0.571, 95% CI = 0.175-1.865, P < 0.001). The rs7574865 variant in STAT4 (G/T) occurred frequently in both HCV groups, with a significant incidence risk (OR = 1.583, 95% CI = 1.123-2.232, P = 0.005). The rs5742909 change in CTLA4 (C/T) did not show a significant difference between HCV-mediated HCC cases and the control group (OR = 4.5, 95% CI = 1.326-15.277, P > 0.001). Activation of the immune checkpoint gene CTLA4 or polymorphism in the encoded CTLA4 protein causes phosphorylation of kinases needed for RAS gene activation. This in turn downregulates the tumor suppressor RASSF1, inhibiting apoptosis and leading to HCC development, indicating a negative impact of CTLA4 gene polymorphism on HCV-mediated HCC cases. A major determinant of disease progression could be immune system genetic variants, together with the presence of costimulatory factors. The rs2073498 and rs7574865 variations in the RASSF1A and STAT4 genes, respectively, could be genetic susceptibility factors for Egyptian patients with HCV-mediated HCC.


Assuntos
Antígeno CTLA-4/metabolismo , Carcinoma Hepatocelular/virologia , Hepatite C/complicações , Neoplasias Hepáticas/virologia , Fator de Transcrição STAT4/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Hepacivirus , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fator de Transcrição STAT4/genética , Proteínas Supressoras de Tumor/genética , Carga Viral
19.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917711

RESUMO

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.


Assuntos
Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Suscetibilidade a Doenças , Proteínas Supressoras de Tumor/genética , Idoso , Biomarcadores , Biópsia , Doenças do Sistema Nervoso Central/diagnóstico , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo
20.
Radiol Clin North Am ; 59(3): 305-322, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33926679

RESUMO

Molecular features are now essential in distinguishing between glioma histologic subtypes. Currently, isocitrate dehydrogenase mutation, 1p19q codeletion, and MGMT methylation status play significant roles in optimizing medical and surgical treatment. Noninvasive pretreatment and post-treatment determination of glioma subtype is of great interest. Although imaging cannot replace the genetic panel at present, image findings have shown promising signs to identify and diagnose the types and subtypes of gliomas. This article details key imaging findings in the most common molecular glioma subtypes and highlights recent advances in imaging technologies to differentiate these lesions noninvasively.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Isocitrato Desidrogenase/genética , Imageamento por Ressonância Magnética/métodos , Mutação/genética , Tomografia Computadorizada por Raios X/métodos , Proteínas Supressoras de Tumor/genética , Encéfalo/diagnóstico por imagem , Humanos , Metilação
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