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1.
Adv Exp Med Biol ; 1287: 169-181, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034032

RESUMO

The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.


Assuntos
Progressão da Doença , Neoplasias/patologia , Receptores Notch , Transdução de Sinais , Genes Supressores de Tumor , Humanos , Neoplasias/genética , Oncogenes , Receptores Notch/metabolismo
2.
Adv Exp Med Biol ; 1255: 99-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949393

RESUMO

Lung carcinoma is the most frequently diagnosed malignant neoplasms and mainly consists of small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Large number of lung carcinoma patients have poor outcomes due to the late diagnosis and the limited therapeutic options. Previous attempts have proved that the evolution of lung carcinoma is a multistep molecular aberration which various genetic or epigenetic alterations may be take part in. Among these molecular aberrations, the inactivation of tumor suppressor gene has been widely observed in all types of carcinoma including lung carcinoma. As a vital inactivated mechanism, DNA methylation of tumor suppressor gene is frequently found in lung cancer. To gain exhaustive comprehension of the carcinogenesis of lung carcinoma, we summarize our current knowledge on DNA methylation of RASSF1 (RAS-Association Domain Family 1) and its clinical significance in lung carcinoma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Genes Supressores de Tumor , Humanos
3.
Adv Exp Med Biol ; 1255: 123-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949395

RESUMO

Hypermethylation can downregulate many tumor suppressor gene expressions. Aplasia Ras homologue member I (ARHI, DIRAS3) is one of the maternally imprinted tumor suppressors in the RAS superfamily. This chapter overviewed the importance of ARHI methylation and expression phenomes in various types of cancers, although the exact mechanisms remain unclear. As an imprinted gene, aberrant DNA methylation of the paternal allele of ARHI was identified as a primary inhibitor of ARHI expression. The role of methylation in the CpG islands of the ARHI promoter region vary among ovarian cancers, breast cancers, hepatocellular carcinoma, colon cancers, pancreatic cancer osteosarcoma, glial tumors, follicular thyroid carcinoma, or lung cancers. The methylation of ARHI provides a new insight to understand molecular mechanisms of tumorigenesis and progression of cancers.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Neoplasias/genética , Regiões Promotoras Genéticas , Proteínas rho de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos
4.
Nat Commun ; 11(1): 4063, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792525

RESUMO

The neuroendocrine hypothalamus is the central regulator of vital physiological homeostasis and behavior. However, the cellular and molecular properties of hypothalamic neural progenitors remain unexplored. Here, hypothalamic radial glial (hRG) and hypothalamic mantle zone radial glial (hmRG) cells are found to be neural progenitors in the developing mammalian hypothalamus. The hmRG cells originate from hRG cells and produce neurons. During the early development of hypothalamus, neurogenesis occurs in radial columns and is initiated from hRG cells. The radial glial fibers are oriented toward the locations of hypothalamic subregions which act as a scaffold for neuronal migration. Furthermore, we use single-cell RNA sequencing to reveal progenitor subtypes in human developing hypothalamus and characterize specific progenitor genes, such as TTYH1, HMGA2, and FAM107A. We also demonstrate that HMGA2 is involved in E2F1 pathway, regulating the proliferation of progenitor cells by targeting on the downstream MYBL2. Different neuronal subtypes start to differentiate and express specific genes of hypothalamic nucleus at gestational week 10. Finally, we reveal the developmental conservation of nuclear structures and marker genes in mouse and human hypothalamus. Our identification of cellular and molecular properties of neural progenitors provides a basic understanding of neurogenesis and regional formation of the non-laminated hypothalamus.


Assuntos
Hipotálamo/citologia , Hipotálamo/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Animais , Análise por Conglomerados , Feminino , Genes Supressores de Tumor , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Hibridização In Situ , Mamíferos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neurogênese/genética , Neurogênese/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Gravidez
5.
Cell Prolif ; 53(8): e12856, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32648622

RESUMO

OBJECTIVES: Glial cell activation contributes to the inflammatory response and occurrence of epilepsy. Our preliminary study demonstrated that the long non-coding RNA, H19, promotes hippocampal glial cell activation during epileptogenesis. However, the precise mechanisms underlying this effect remain unclear. MATERIALS AND METHODS: H19 and let-7b were overexpressed or silenced using an adeno-associated viral vector in vivo. Their expression in a kainic acid-induced epilepsy model was evaluated by real-time quantitative PCR, fluorescence in situ hybridization, and cytoplasmic and nuclear RNA isolation. A dual-luciferase reporter assay was used to evaluate the direct binding of let-7b to its target genes and H19. Western blot, video camera monitoring and Morris water maze were performed to confirm the role of H19 and let7b on epileptogenesis. RESULTS: H19 was increased in rat hippocampus neurons after status epilepticus, which might be due to epileptic seizure-induced hypoxia. Increased H19 aggravated the epileptic seizures, memory impairment and mossy fibre sprouting of the epileptic rats. H19 could competitively bind to let-7b to suppress its expression. Overexpression of let-7b inhibited hippocampal glial cell activation, inflammatory response and epileptic seizures by targeting Stat3. Moreover, overexpressed H19 reversed the inhibitory effect of let-7b on glial cell activation. CONCLUSIONS: LncRNA H19 could competitively bind to let-7b to promote hippocampal glial cell activation and epileptic seizures by targeting Stat3 in a rat model of temporal lobe epilepsy.


Assuntos
Epilepsia do Lobo Temporal/genética , Hipocampo/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Genes Supressores de Tumor/fisiologia , Masculino , Ratos Sprague-Dawley , Convulsões/genética , Convulsões/metabolismo
6.
Environ Sci Pollut Res Int ; 27(30): 38300-38310, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621200

RESUMO

Toxic and apoptotic impacts of zinc oxide nanoparticle (ZNP) on different cancer cells have been reported. Maspin (a mammary serine protease inhibitor) as a tumor suppressor gene can inhibit tumor growth and metastasis. The expression of maspin is modulated by p53, Bcl-2 family genes, and estrogen receptor α (ER-α). This study aimed to assess the ZNP effects on maspin expression in MCF-7 cells (a breast cancer cell). Experimental groups (ZNP5, ZNP10, and ZNP20) received 5, 10, and 20 µM/mL ZNP for 48 h, respectively. 17-ß-estradiol (E2) was used to evaluate the role of ER-α in the anticancer impact of ZNP. Cell viability, Annexin V, migration assay, gene expression, and western blotting methods were applied to evaluate ZNP effects on the MCF-7 cells. ZNP at the concentrations of 10 and 20 µM/mL could significantly decrease the viability and migration rate, and significantly increase apoptosis percentage in the MCF-7 cells. ZNP significantly enhanced mRNA expression and protein level of maspin in MCF-7 cells in a concentration-dependent way. ZNP concentration-dependently elevated mRNA expression and protein level of p53 and Bax while reduced the expression of Bcl-2 and ER-α. E2 promoted cancer cell growth by enhancing survival and migration rates. E2 treatment reduced mRNA expression and protein level of maspin and p53, and elevated Bcl-2 expression. ZNP considerably changed these events induced by E2 in the MCF-7 cells. It is concluded that the maspin overexpression is one of the toxic mechanisms of the ZNP on the ER-α-positive breast cancer cells, and can suppress the migration of these cells.


Assuntos
Neoplasias da Mama/genética , Nanopartículas , Óxido de Zinco , Genes Supressores de Tumor , Humanos , Serpinas
7.
Life Sci ; 258: 118134, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717272

RESUMO

Cancer can arise due to mutations in numerous pathways present in our body and thus has many alternatives for getting aggravated. Due to this attribute, it gets difficult to treat cancer patients with monotherapy alone and has a risk of not being eliminated to the full extent. This necessitates the introduction of combinatorial therapy as it employs cancer treatment using more than one method and shows a greater success rate. Combinatorial therapy involves a complementary combination of two different therapies like a combination of radio and immunotherapy or a combination of drugs that can target more than one pathway of cancer formation like combining CDK targeting drugs with Growth factors targeting drugs. In this review, we discuss the various aspects of cancer which include, its causes; four regulatory mechanisms namely: apoptosis, cyclin-dependent kinases, tumor suppressor genes, and growth factors; some of the pathways involved; treatment: monotherapy and combinatorial therapy and combinatorial drug formulation in chemotherapy. The present review gives a holistic account of the different mechanisms of therapies and also drug combinations that may serve to not only complement the monotherapy but can also surpass the resistance against monotherapy agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Progressão da Doença , Composição de Medicamentos , Genes Supressores de Tumor , Humanos , Neoplasias/genética , Neoplasias/patologia , Vírus Oncogênicos/fisiologia
8.
Medicine (Baltimore) ; 99(24): e20445, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541467

RESUMO

BACKGROUND: The global morbidity of cancer is rising rapidly. Despite advances in molecular biology, immunology, and cytotoxic and immune-anticancer therapies, cancer remains a major cause of death worldwide. Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a new member of the cytoplasmic protein tyrosine phosphatase family, isolated from a cDNA library of adult colon tissue. Thus far, no studies have reviewed the correlation between PTPN12 gene expression and human tumors. METHODS: This article summarizes the latest domestic and international research developments on how the expression of PTPN12 relates to human tumors. The extensive search in Web of Science and PubMed with the keywords including PTPN12, tumor, renal cell carcinoma, proto-oncogenes, tumor suppressor genes was undertaken. RESULTS: More and more studies have shown that a tumor is essentially a genetic disease, arising from a broken antagonistic function between proto-oncogenes and tumor suppressor genes. When their antagonistic effect is out of balance, it may cause uncontrolled growth of cells and lead to the occurrence of tumors. PTPN12 is a tumor suppressor gene, so inhibiting its activity will lead directly or indirectly to the occurrence of tumors. CONCLUSION: The etiology, prevention, and treatment of tumors have become the focus of research around the world. PTPN12 is a tumor suppressor gene. In the future, PTPN12 might serve as a novel molecular marker to benefit patients, and even the development of tumor suppressor gene activation agents can form a practical research direction.


Assuntos
Genes Supressores de Tumor , Proteína Tirosina Fosfatase não Receptora Tipo 12/genética , Humanos , Neoplasias/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 12/metabolismo
9.
J Cancer Res Clin Oncol ; 146(7): 1781-1789, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32361787

RESUMO

INTRODUCTION: EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes. METHODS: From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed. RESULTS: The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018). CONCLUSIONS: Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Biomarcadores Tumorais , Genes Supressores de Tumor , Mutação , Receptores ErbB/genética , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Modelos de Riscos Proporcionais , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Exoma
10.
Anticancer Res ; 40(5): 2675-2685, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366412

RESUMO

BACKGROUND/AIM: To evaluate the anti-cancer mechanism of N-Farnesyl-norcantharimide (NC15). MATERIALS AND METHODS: The viability of NC15-treated human leukemic Jurkat T (JKT) cells was assessed using the Kit-8 cell counting method. Flow cytometry analysis, human apoptosis antibody array assay, and whole genome sequencing were adopted to investigate the mechanism underlying the anti-cancer activity of NC15 in JKT cells. RESULTS: The growth inhibition rates of NC15 in JKT cells were about 80% and 95% after treatment with 8 µmol/l NC15 for 24 and 48 h, respectively. The percentages of NC15-treated JKT cells in the sub-G1 phase at 24 and 48 h were 22.0% and 34.3%, respectively, in contrast to the 1.5% in the control. Next-generation sequencing showed that many tumor suppressor genes (TSG) were up-regulated, while many genes associated with steroid biosynthesis, metabolic pathways, and fatty acid metabolism were down-regulated. CONCLUSION: NC15 can reduce the cell viability and increase the percentage of JKT cells in the sub-G1 phase by up-regulating TSG and related genes, and down-regulating the genes for steroid biosynthesis, metabolic pathways and fatty acid metabolism, instead of through apoptosis.


Assuntos
Cantaridina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Genes Supressores de Tumor , Redes e Vias Metabólicas/genética , Esteroides/biossíntese , Linfócitos T/citologia , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Cantaridina/química , Cantaridina/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação para Baixo/genética , Humanos , Células Jurkat , Redes e Vias Metabólicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Regulação para Cima/genética
11.
Hum Cell ; 33(3): 641-651, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32419118

RESUMO

MiR-27b-3p has been reported to function as tumor suppressor in several tumors, including breast cancer and lung cancer. Recently, miR-27b-3p has been identified to be significantly down-regulated in esophageal cancer. However, the clinical significance and biological role of miR-27b-3p in esophageal squamous cell carcinoma (ESCC) still remain unclear. In this study, the expression levels of miR-27b-3p were significantly reduced in ESCC clinical tissues and ESCC cell lines (EC97069 and TE-1). Moreover, down-regulated expression of miR-27b-3p was associated with poor cell differentiation, TNM stage and lymph node metastasis. Specially, overexpression of miR-27b-3p significantly suppressed cell proliferation, migration and invasion in vitro using CCK-8 and transwell assays. Targetscan bioinformatics predictions and luciferase reporter assay confirmed that nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) was a direct target gene of miR-27b-3p. Nrf2 expression was significantly increased in ESCC tissues compared with adjacent tissues. Up-regulated expression of Nrf2 was correlated with TNM stage and lymph node metastasis. Functionally, knockdown of Nrf2 exhibited similar effects to overexpression of miR-27b-3p. Higher expression of ZO-1, E-cadherin and lower expression of N-cadherin, Vimentin and Claudin-1 were observed after miR-27b-3p overexpression of Nrf2 knockdown. Rescue experiments proved that miR-27b-3p suppressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT) via suppression of Nrf2. Taken together, the newly identified miR-27b-3p/Nrf2 axis might represent a new candidate therapeutic target for ESCC treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genes Supressores de Tumor , MicroRNAs/genética , MicroRNAs/fisiologia , Fator 2 Relacionado a NF-E2/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/genética
12.
Nucleic Acids Res ; 48(12): 6775-6787, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453417

RESUMO

Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2's binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2's activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.


Assuntos
Fator de Transcrição E2F1/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Carcinogênese/genética , Ciclo Celular/genética , Proliferação de Células/genética , Dano ao DNA/genética , Genes Supressores de Tumor , Herpesvirus Humano 4/genética , Humanos , Neoplasias/virologia , Oncogenes/genética , Fosforilação/genética , Domínios Proteicos/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , RNA Mensageiro/genética , Proteína Supressora de Tumor p14ARF/genética
13.
J Cancer Res Ther ; 16(1): 7-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362602

RESUMO

Background: Xist is a long noncoding RNA involved in the X chromosome inactivation in females. It may act as an onco-suppressor gene in hematologic malignancies, and its activity is strongly dependent from SATB1 gene expression. However, its potential role in Hodgkin's disease (HD) onset and progression is unknown. Materials and Methods: Three gene expression microarray datasets were analyzed for the expression of Xist and SATB1 in patients with classical HD, namely, GDS4222 (130 patients and 54,000 gene features), GSE39134 (29 patients and 54,000 features), and E-MEXP-507 (29 patients and 27,648 probes). The first two were oligonucleotide arrays (platform: Affymetrix gene chip HG-U133-Plus2), whereas the latter was a cDNA two-channel array (platform: OncoChip. v2). Summary and time-dependent receiver operating characteristic (ROC) analysis were applied to obtain a summary measure (summary area under the ROC curve [sAUC]) of association between gene expression and unfavorable patient outcome in each probe set. Results: Xist was overexpressed among females in each data set. A slight overexpression was associated with a good prognosis both in males (sAUC = 0.75, 95% confidence interval [CI]: 0.70-0.80) and at a lesser extent, in females (sAUC = 0.64, 95% CI: 0.59-0.69). However, this finding was limited to the analysis of the biggest database (GDS4222). No association was found between Xist and SATB1 expression. Conclusions: A reactivation of Xist might act as an onco-suppressor gene in male patients with HD, which seems independent from SATB1 expression. The possibility that Xist could contribute to the better survival of female patients should also be investigated.


Assuntos
Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , RNA Longo não Codificante/genética , Adulto , Biologia Computacional/métodos , Progressão da Doença , Feminino , Doença de Hodgkin/metabolismo , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
14.
Med Sci Monit ; 26: e921659, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248204

RESUMO

BACKGROUND ZW10 binding factor (ZWINT) has been reported to be upregulated in various human cancers and predict worse survival. However, the expression profile, clinical significance, and biological role of ZWINT remains unclear in breast cancer. MATERIAL AND METHODS In this study, we investigated messenger RNA (mRNA) and protein expression levels of ZWINT in breast cancer tissues, and the prognostic value of ZWINT protein expression was validated in a cohort of breast cancer patients using immunohistochemistry analysis. Then, different bioinformatic analyses were combined to explore the potential cancer-related hallmark underlying ZWINT in breast cancer, and a series of experiments in vitro were performed to reveal the oncogenic role of ZWINT in breast cancer. RESULTS Significant upregulation of ZWINT was observed in breast cancer tissues compared to normal and para-tumor tissues and upregulation of ZWINT predicts poor prognosis in breast cancer patients. Additionally, ZWINT could promote breast cancer proliferation via cell cycle regulation, especially by influencing the expression of some critical cell cycle regulators involved in G1 phase and G1/S transition. Finally, miR-204 was identified as a tumor suppressor microRNA which directly targets a specific site in 3'-UTR of ZWINT. CONCLUSIONS Overall, our results indicated that miR-204/ZWINT/cell cycle process might play an important role in breast cancer progression.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Regiões 3' não Traduzidas , Ciclo Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Imuno-Histoquímica , MicroRNAs , Proteínas Nucleares , Prognóstico , Análise de Sobrevida , Regulação para Cima
15.
Arch Biochem Biophys ; 686: 108367, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315652

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatocellular carcinoma, and microRNAs (miRNAs) play a vital role in its development. This study aimed to explore the molecular mechanism and clinical value of miR-19b-3p in ICC. METHODS: From March 2014 to October 2016, 94 pairs of specimens of ICC tissues and adjacent tissues were collected. Moreover, 5 ml of peripheral blood of 342 ICC patients who underwent ICC resection were collected before and one week after surgery. Luciferase activity assay was performed to confirm the regulation of miR-19b-3p on coiled-coil domain containing 6 (CCDC6). BALB/c nude mice were injected with CCLP-1 cells which were transfected with NC, miR-19b-3p mimic, miR-19b-3p inhibitor, pcDNA-CCDC6, si-CCDC6 or miR-19b-3p mimic + pcDNA-CCDC6. RESULTS: Results showed that miR-19b-3p levels were significantly higher in ICC tissues compared with adjacent tissues. Moreover, serum miR-19b-3p levels of ICC patients tended to decline after surgery, and were correlated with lymph node metastasis and histological grading of ICC. CCDC6, a new target gene of miR-19b-3p, was identified by four prediction databases. We confirmed that miR-19b-3p promoted cell proliferation and epithelial-mesenchymal transition (EMT), and inhibited apoptosis in ICC, while knockdown of CCDC6 reversed these effects. We also observed that miR-19b-3p/CCDC6 axis regulated the nuclear translocation of ß-catenin. Furthermore, in vivo study also demonstrated that the miR-19b-3p/CCDC6 axis regulated EMT to promote ICC progression. CONCLUSION: These results indicate that serum miR-19b-3p level is a crucial biomarker for ICC diagnosis and targeting miR-19b-3p-CCDC6 axis might be a promising strategy in ICC therapy.


Assuntos
Carcinoma Hepatocelular/genética , Colangiocarcinoma/genética , Proteínas do Citoesqueleto/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/metabolismo , Proteínas do Citoesqueleto/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
16.
Prostate ; 80(8): 640-652, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32282098

RESUMO

BACKGROUND: Androgen receptor (AR) is crucial for prostate cancer (PCa) initiation and malignant progression. Only half of androgen-responsive genes have been identified as having androgen-responsive elements, suggesting that AR regulates downstream genes through other transcriptional factors. However, whether and how AR regulates the progression via regulating these androgen-responsive genes remains unclear. METHODS: Androgen-responsive and activity-changed (AC) transcriptional factors (TFs) were identified based on the time-course gene-expression array and gene promoter regions analysis. The intersection of androgen-responsive and AC TFs was selected the core TFs, which were used to construct the core transcriptional regulatory network. GO enrichment analysis, cell proliferation assays, glycolysis experiments, and reverse transcription polymerase chain reaction analysis were used to analyze and validate the functions of the network. As one of the core TFs, the function and mechanism of IRF1 have been further explored. RESULTS: We devised a new integrated approach to select core TFs and construct core transcriptional regulatory network in PCa. The 24 core TFs and core transcriptional regulatory network participate in regulating PCa cell proliferation, RNA splicing, and cancer metabolism. Further validations showed that AR signaling could promote glycolysis via inducing glycolytic enzymes in PCa cells. IRF1, a novel target of AR, served as a tumor suppressor by inhibiting PCa proliferation, cell cycle, and glycolysis. CONCLUSIONS: It is the first time to demonstrate the regulating role of the AR-mediated transcriptional regulatory network in a series of important biological processes in PCa cells. IRF1, an AR-regulated TF, acts as tumor suppressor in this core transcriptional regulatory network, which highlights the therapeutic potential of targeting this regulatory network for PCa.


Assuntos
Redes Reguladoras de Genes , Fator Regulador 1 de Interferon/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Genes Supressores de Tumor , Glicólise , Humanos , Fator Regulador 1 de Interferon/metabolismo , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo
17.
Hum Cell ; 33(3): 437-443, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32274657

RESUMO

StarD13 is a tumor suppressor and a GTPase activating protein (GAP) for Rho GTPases. Thus, StarD13 regulates cell survival pathways and induces apoptosis in a p53-dependent and independent manners. In tumors, StarD13 is either downregulated or completely inhibited, depending on the tumor type. As such, and through the dysregulation of Rho GTPases, this affects adhesion dynamics, actin dynamics, and leads to an increase or a decrease in tumor metastasis depending on the tumor grade and type. Being a key regulatory protein, StarD13 is a potential promising candidate for therapeutic approaches. This paper reviews the key characteristics of this protein and its role in tumor malignancies.


Assuntos
Proteínas Ativadoras de GTPase/genética , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Supressoras de Tumor/genética , Sequência de Aminoácidos , Regulação para Baixo , Proteínas Ativadoras de GTPase/química , Proteínas Ativadoras de GTPase/metabolismo , Genes Supressores de Tumor , Humanos , Neoplasias/patologia , Proteína Supressora de Tumor p53 , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo , Proteínas rho de Ligação ao GTP
18.
Adv Exp Med Biol ; 1233: 29-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274752

RESUMO

Ubiquitin defines a family of approximately 20 peptidic posttranslational modifiers collectively called the Ubiquitin-like (UbLs). They are conjugated to thousands of proteins, modifying their function and fate in many ways. Dysregulation of these modifications has been implicated in a variety of pathologies, in particular cancer. Ubiquitin, SUMO (-1 to -3), and Nedd8 are the best-characterized UbLs. They have been involved in the regulation of the activity and/or the stability of diverse components of various oncogenic or tumor suppressor pathways. Moreover, the dysregulation of enzymes responsible for their conjugation/deconjugation has also been associated with tumorigenesis and cancer resistance to therapies. The UbL system therefore constitutes an attractive target for developing novel anticancer therapeutic strategies. Here, we review the roles and dysregulations of Ubiquitin, SUMO, and Nedd8 pathways in tumorigenesis, as well as recent advances in the identification of small molecules targeting their conjugating machineries for potential application in the fight against cancer.


Assuntos
Terapia de Alvo Molecular , Proteína NEDD8/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteína SUMO-1/antagonistas & inibidores , Ubiquitina/antagonistas & inibidores , Genes Supressores de Tumor , Humanos , Neoplasias/genética
19.
J Cancer Res Clin Oncol ; 146(4): 897-907, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146565

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS: The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS: Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION: Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.


Assuntos
Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Pancreáticas/genética , Proteína C-Reativa/genética , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Diferenciação Celular/genética , DNA Tumoral Circulante/sangue , Encefalinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Osteonectina/genética , Neoplasias Pancreáticas/sangue , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ubiquitina Tiolesterase/genética
20.
J Biol Regul Homeost Agents ; 34(1): 101-110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148011

RESUMO

MicroRNAs (miRNAs) have been demonstrated to have promoting or inhibiting effects on the tumorigenesis of multiple cancers, including ovarian cancer (OC), by regulating its downstream target genes. In the presented experiment, our aim was to explore the role of miR-543 in OC cell proliferation and invasion. Results of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot revealed that miR-543 have lower expression levels, while Twist homolog 1 (TWIST1) was expressed with higher levels in OC tissues and cells. Furthermore, the effects of abnormal miR-543 expression in OC cell proliferation and invasion were detected by CCK-8 and Transwell assay. According to luciferase reporter assay results, TWIST1 was identified as a downstream target of miR-543 in OC, and a negative correlation was observed between TWIST1 and miR-543 expression by Spearman's correlation analysis in OC tissues. In addition, TWIST1 may reverse the miR-543 suppression effect on OC cell proliferation and invasion. To sum up, miR-543 may promote OC cell proliferation and invasion by targeting TWIST1.


Assuntos
Genes Supressores de Tumor , MicroRNAs/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Proteína 1 Relacionada a Twist/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica
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