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1.
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
2.
Gene ; 726: 144176, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669641

RESUMO

Gastric cancer is a serious problem for human health. As part of noncoding RNA, circular RNA (circRNA) plays a key role in the occurrence and development of malignant tumor. We used next generation sequencing technology to detect circRNA expression profiles in 5 paired human gastric cancer tissues. Then, bioinformatics analysis was carried out to analyze the function of dysregulated circRNAs. Hsa_circ_0058092 was selected as the object of follow-up analysis. After using the Cistrome DB dataset the data was used to predict specific transcription factors of hsa_circ_0058092. The relationship between hsa_circ_0058092 and PODXL was further validated using RT-PCR and immunohistochemical techniques. Survival data were collected using a Kaplan-Meier analysis of hsa_circ_0058092. We identified 319 aberrantly expressed circRNAs, Hsa_circ_0058092 was selected for our studies. Functional analysis of hsa_circ_0058092 revealed that it was related to metabolic processes. The prediction results suggested that hsa_circ_0058092 has a relationship with hsa-miR-4269 which could specifically bind to the PODXL sequence. Transcription factor CEBPB may regulate the transcription process of hsa_circ_0058092. The expression of hsa_circ_0058092 was positively correlated with PODXL expression. Immunohistochemical analysis of PODXL showed that the expression of PODXL protein in cancer tissues is higher than that in adjacent tissues. Kaplan-Meier analysis suggested that hsa_circ_0058092 was associated with survival of gastric cancer patients. All of these results showed that hsa_circ_0058092 was a potential oncogene.


Assuntos
Oncogenes/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA não Traduzido/genética , Sialoglicoproteínas/genética , Fatores de Transcrição/genética , Transcrição Genética/genética
4.
Int J Cancer ; 146(1): 208-222, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251822

RESUMO

The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas/patologia , Oncogenes , Proteínas Tirosina Quinases/fisiologia , Sistemas CRISPR-Cas , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , Proteínas Tirosina Quinases/genética
5.
J Cancer Res Clin Oncol ; 145(12): 2901-2910, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31654122

RESUMO

INTRODUCTION: The nuclear pore complex is comprised of approximately 30 proteins named nucleoporins (Nups) and tightly regulates nucleocytoplasmic transport of macromolecules across the nuclear membrane. Genetic alterations in many NUP genes are associated with many human maladies, such as neurological disease, autoimmune disorders and cancer. METHODS: We reviewed the status quo of recent advancement of the knowledge of oncogenic role of nucleoporins in human carcinogenesis, focusing on major non-hematological malignancies in the recent literature. Both clinical study-derived and experiment-based reports were critically reviewed. We have also discussed the potential of nucleoporins as novel cancer biomarkers and promising therapeutic target against human malignancies. RESULTS: Several Nups such as Nup53, Nup88, Nup98, Nup160 and Nup214 modulated a plethora of cellular and physiological pathways involved in tumorigenesis such as GSK3ß-Snail, Wnt/ß-Catenin and RanGap1/RanBP2 signaling axes, DNA damage response, resistance to apoptosis and chemotherapy. CONCLUSION: Although classically, majority of studies have shown oncogenic roles of nucleoporins as genetic fusion partners in several types of leukemia, emerging evidence suggests that nucleoporins also modulate many cellular signaling pathways that are associated with several major non-hematological malignancies, such as carcinomas of skin, breast, lung, prostate and colon. Hence, nucleoporins are emerging as novel therapeutic targets in human tumors.


Assuntos
Cromossomos/genética , Fusão Gênica/genética , Neoplasias/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Oncogenes/genética , Translocação Genética/genética , Animais , Humanos
6.
J Biochem Mol Toxicol ; 33(12): e22411, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621980

RESUMO

To date, microRNA-4709 (miR-4709) has not been studied in colon adenocarcinoma (COAD) on the basis of experiments. In our study, we aimed to investigate the biological roles and clinical significance of miR-4709 in COAD. The expression difference between miR-4709 and NR3C2 was measured based on The Cancer Genome Atlas database and cells. Kaplan-Meier and logrank tests were applied to determine the overall survival (OS) differences according to the miR-4709 and NR3C2 expression levels. To measure whether the miR-4709 level was associated with COAD cell growth, migration, and invasion, we respectively conducted 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and transwell assays. A luciferase reporter assay was applied to confirm the relationship between miR-4709 and its predicted target. High expression of miR-4709 was found in COAD tissues and cells. The OS rate in the miR-4709 low expression group was significantly higher than that in the miR-4709 high expression group. Univariate and multivariate analyses exhibited that miR-4709 expression was an independent adverse prognostic factor. Exogenous miR-4709 overexpression promoted proliferation, migration, and invasion of LOVO and SW480 cells. Bioinformatics analysis and luciferase assay demonstrated that miR-4709 directly binds to the 3'-untranslated region of NR3C2. NR3C2 was lowly expressed in COAD and high expression of NR3C2 had a better prognosis compared with that in the low expression of NR3C2. Correlation analysis showed that there is a close association between the level of expression of NR3C2 and miR-4709. Accordingly, miR-4709 may function as an oncogene in COAD and provide a preclinical proof for candidate management to target new miR-4709-NR3C2 signaling for COAD therapy.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , MicroRNAs/metabolismo , Receptores de Mineralocorticoides/metabolismo , Regiões 3' não Traduzidas , Adenocarcinoma/metabolismo , Antagomirs , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Oncogenes , Prognóstico , Taxa de Sobrevida , Transfecção
7.
Cancer Discov ; 9(10): 1346-1348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31575564

RESUMO

Identification of cancer-associated mutations in core histone genes has proved challenging due to these genes' highly conserved nature and presence in large arrays. Recent analyses of cancer genomes, including one in this issue of Cancer Discovery, show that mutations in the histone fold can affect nucleosome stability, providing a novel mechanism by which oncohistones contribute to tumorigenesis.See related article by Bennett et al., p. 1438.


Assuntos
Histonas/genética , Nucleossomos , Carcinogênese/genética , Humanos , Mutação , Oncogenes
8.
Anticancer Res ; 39(10): 5311-5327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570425

RESUMO

BACKGROUND/AIM: MiR-221, often described both as an oncogenic microRNA and as a tumour suppressor, targets mRNAs involved in carcinogenesis. While other oncogenic microRNAs showed correlations with prostate cancer cell lines' aggressiveness, miR-221 showed an unusual overexpression in PC3. MATERIALS AND METHODS: CRISPR was used to delete miR-221 from PC3 cells. Analysing the characteristics of PC3miR-221del cells, a reduced growth rate and expression of cell-cycle genes was observed. In global gene expression/ontology analysis of PC3miR-221del cells, cell-cell and cell-substrate adhesion pathways were found to be greatly affected. In addition, reduced levels of adhesion, invasion and motility for PC3miR-221del cells, a change in F-actin localisation and a reduction of EMT markers were observed. RESULTS: The tumour suppressor gene, DIRAS3, was a predicted target of miR-221. In PC3miR-221del cells DIRAS3 was up-regulated at the gene and protein level. Ectopic expression of DIRAS3 in PC3wt cells recapitulated the cellular morphology changes seen in PC3miR-221del cells. DIRAS3 3'UTR was more stable in PC3miR-221del cells, as measured by semi-quantitative PCR and luciferase fusion reporter assays. CONCLUSION: MiR-221 promotes aggressiveness of PC3 cells by down-regulating DIRAS3, and promoting epithelial-to-mesenchymal transition.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Oncogenes/genética , Células PC-3 , Neoplasias da Próstata/genética , Regulação para Cima/genética , Proteínas rho de Ligação ao GTP/genética
9.
Anticancer Res ; 39(10): 5345-5352, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570428

RESUMO

BACKGROUND/AIM: Accurate and timely assessment of the human epidermal growth factor receptor 2 (HER2/neu) overexpression is pivotal for the identification of breast cancer (BC) patients that could benefit from HER2-targeted therapy. Currently approved tissue-based HER2 assays (tHER2) are limited to testing HER2 status on tumor samples obtained at a few points in time during the course of the disease. Herein, we assessed serum HER2 (sHER2) status longitudinally in 81 serial samples prospectively collected from 43 consenting patients pre- and post-therapy to revisit the idea of serum testing in the follow-up of BC patients. PATIENTS AND METHODS: The cohort included 11 patients with early BC (EBC), 17 with locally advanced BC (LABC), and 15 with metastatic BC (MBC). sHER2 concentrations were measured using a quantitative ELISA-based technique, using 15 ng/ml as the cut-off for positivity. RESULTS: At baseline, sHER2 was negative in all EBC patients while positive in 1 LABC and 5 MBC patients. Sixteen BC patients (10 LABC, 1 EBC, and 5 MBC) were tHER2 positive. sHER2 and tHER2 results were discordant in 14 patients. Among the 16 tHER2 positive patients, 9 LABC, 1 EBC and 2 MBC patients were sHER2 negative. Conversely, 2 MBC patients were sHER2 positive, despite being tHER2 negative. A rise or drop of sHER2 by >20% correlated with disease progression or pathological response to therapy, respectively. CONCLUSION: The study demonstrated the technical validity and feasibility of the sHER2 assay. Findings suggest that post initial tissue diagnosis (tHER2), sHER2 assay may supplement subsequent tissue tests to monitor disease status and response to therapy. Further studies to assess the role of HER2 targeted therapies in sHER-positive/tHER2-negative cases upon disease progression are warranted.


Assuntos
Neoplasias da Mama/sangue , Receptor ErbB-2/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Oncogenes/genética , Projetos Piloto
10.
Anticancer Res ; 39(10): 5789-5795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570483

RESUMO

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. PATIENTS AND METHODS: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. RESULTS: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). CONCLUSION: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.


Assuntos
Antígeno B7-H1/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncogenes/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
11.
PLoS Comput Biol ; 15(9): e1007381, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31568528

RESUMO

Cancer driver genes, i.e., oncogenes and tumor suppressor genes, are involved in the acquisition of important functions in tumors, providing a selective growth advantage, allowing uncontrolled proliferation and avoiding apoptosis. It is therefore important to identify these driver genes, both for the fundamental understanding of cancer and to help finding new therapeutic targets or biomarkers. Although the most frequently mutated driver genes have been identified, it is believed that many more remain to be discovered, particularly for driver genes specific to some cancer types. In this paper, we propose a new computational method called LOTUS to predict new driver genes. LOTUS is a machine-learning based approach which allows to integrate various types of data in a versatile manner, including information about gene mutations and protein-protein interactions. In addition, LOTUS can predict cancer driver genes in a pan-cancer setting as well as for specific cancer types, using a multitask learning strategy to share information across cancer types. We empirically show that LOTUS outperforms five other state-of-the-art driver gene prediction methods, both in terms of intrinsic consistency and prediction accuracy, and provide predictions of new cancer genes across many cancer types.


Assuntos
Algoritmos , Biologia Computacional/métodos , Aprendizado de Máquina , Neoplasias/genética , Oncogenes/genética , Software , Humanos , Modelos Estatísticos
12.
Adv Exp Med Biol ; 1167: 15-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520347

RESUMO

The formation, overgrowth and metastasis of tumors comprise a complex series of cellular and molecular events resulting from the combined effects of a variety of aberrant signaling pathways, mutations, and epigenetic alterations. Modeling this complexity in vivo requires multiple genes to be manipulated simultaneously, which is technically challenging. Here, we analyze how Drosophila research can further contribute to identifying pathways and elucidating mechanisms underlying novel cancer driver (risk) genes associated with tumor growth and metastasis in humans.


Assuntos
Drosophila , Neoplasias , Oncogenes , Animais , Modelos Animais de Doenças , Humanos , Mutação , Transdução de Sinais
13.
Adv Exp Med Biol ; 1167: 157-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520354

RESUMO

MiRNAs are post-transcriptional regulators of gene expression which have been implicated in virtually all biological processes. MiRNAs are frequently dysregulated in human cancers. However, the functional consequences of aberrant miRNA levels are not well understood. Drosophila is emerging as an important in vivo tumor model, especially in the identification of novel cancer genes. Here, we review Drosophila studies which functionally dissect the roles of miRNAs in tumorigenesis. Ultimately, these advances help to understand the implications of miRNA dysregulation in human cancers.


Assuntos
Drosophila , MicroRNAs/genética , Neoplasias/genética , Animais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Oncogenes
14.
Med Sci Monit ; 25: 6872-6883, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31515467

RESUMO

BACKGROUND Worldwide, dietary changes have resulted in an increased incidence of colorectal cancer (CRC). Circular RNAs (circRNAs) are involved in tumorigenesis of several human tumors, but their role in CRC remains unknown. This study aimed to investigate the expression and effects of Homo sapiens (hsa)_circ_0079993 of POLR2J4 and its impact on CRC. MATERIAL AND METHODS Paired CRC tissue and adjacent normal colorectal tissue samples (N=41), and HCT116 and SW620 human CRC cells were studied. The expression of circ_0079993 and its parental gene, POLR2J4, were examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Two small-interfering RNAs (siRNAs) against circ_0079993 were used to silence circ_0079993 expression in HCT116 and SW620 CRC cells. Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay, colony formation, and in vivo tumor growth assays. The target miRNAs of circ_0079993 was predicted using TargetScan, and the interaction between circ_0079993 and its target miRNAs were verified by the dual-luciferase reporter (DLR) assay. RESULTS In CRC tissue POLR2J4 expression was reduced, and circ_0079993 expression was increased compared with normal tissue. Knockdown of circ_0079993 significantly inhibited the proliferation of CRC cells in vitro. Also, circ_0079993 was predicted to sponge multiple miRNAs, miR-203a-3p.1 was verified as a target of circ_0079993, and circ_0079993 indirectly regulated mRNA expression of the CREB1 gene by sponging miR-203a-3p.1 in CRC cells. The use of anti-miR-203a-3p.1 reversed the inhibitory effects of circ_0079993 knockdown on CRC cell proliferation. CONCLUSIONS The findings supported that hsa_circ_0079993 acts as an oncogene in CRC through the miRNA-203a-3p.1/CREB1 axis.


Assuntos
Neoplasias Colorretais/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MicroRNAs/metabolismo , Oncogenes , RNA Polimerase II/genética , Transdução de Sinais , Algoritmos , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico , RNA Polimerase II/metabolismo , /genética
15.
Cancer Sci ; 110(12): 3821-3833, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31553483

RESUMO

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.


Assuntos
Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Transdução de Sinais/fisiologia , Progressão da Doença , Genes Supressores de Tumor , Humanos , Perda de Heterozigosidade , Mutação , Oncogenes , Fosfatidilinositol 3-Quinases/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
16.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514295

RESUMO

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease.


Assuntos
Adenocarcinoma de Pulmão/genética , MicroRNAs/genética , Oncogenes , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Componente 4 do Complexo de Manutenção de Minicromossomo/genética , Componente 4 do Complexo de Manutenção de Minicromossomo/metabolismo , Análise Multivariada , Invasividade Neoplásica , Fenótipo
17.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 1-5, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472055

RESUMO

Central dogma of molecular biology, a term coined by Francis Crick in 1958 was considered to be the cornerstone of molecular biology unless molecular biologists challenged the idea after ground-breaking discovery of non-coding RNAs. Discovery of microRNAs marked a new era and revolutionized our understanding related to puzzling mysteries about intermediate steps between transcription and translation. Technological advancements have spawned a multitude of platforms for profiling of long-noncoding RNAs and miRNAs in different cancers. Detailed investigation of mRNA targets of miRNAs has enabled high-order analyses of interconnected networks and revealed affected pathways in different cancers. miR-143 has emerged as a multi-talented tumor suppressor microRNA having considerable ability to inhibit and prevent cancer via regulation of myriad of oncogenes. In this review, we will summarize most recent evidence related to characteristically unique ability of miR-143 to target different oncogenic mRNAs in different cancers. We will also comprehensively discuss how scientists have identified multiple long non-coding RNAs reportedly involved in promoting the expression of oncogenes by interfering with miR-143 mediated targeting of these oncogenes. Because of excellent ability of miR-143 to effectively target oncogenic mRNAs, researchers have started to focus on use of miR-143 mimics to restore expression of miR-143 in various cancers.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Animais , Genes Supressores de Tumor , Humanos , MicroRNAs/metabolismo , Oncogenes , RNA Longo não Codificante/metabolismo
18.
Artigo em Chinês | MEDLINE | ID: mdl-31495106

RESUMO

Objective: To study the effect of particulate matter 2.5 (PM(2.5)) on oncogene expression in human bronchial epithelial (HBE) cells. Methods: HBE cells were selected as the study subjects, and PM(2.5) treatment group (10 µg/ml and 50 µg/ml) , negative control group and positive control group (10 µmol/L Cr(6+)) were set. CCK8 assay was used to test the IC(50) value of PM(2.5). HBE cells were treated with PM(2.5) for 24 h at 10 µg/ml and 50 µg/ml, additionally, cells were treated with blank as negative control, 10 µmol/L Cr(6+) as a positive control for 24 h. After the treatment, mRNA expression of oncogenes including c-myc, c-fos, k-ras and p53 were detected by fluorescent quantitative RT-PCR, the protein expression of oncogenes were detected with western blot. Results: The IC(50) value of PM(2.5) in HBE cells is 70.12 µg/ml. The qRT-PCR data showed that compared with the control group, the expression level of c-myc gene increased by respectively 500.1%、780.7%、305.3% after exposure to 10、50 µg/ml PM(2.5) and positive control group; c-fos gene increased respectively 34.0%、76.7%、131.3% after exposure to 10、50 µg/ml PM(2.5) and positive control group; k-ras gene increased respectively 50.3%、107.0%、49.7% after exposure to 10、50 µg/ml PM(2.5) and positive control group; p53 gene decreased by 28.3%、28.7%、59.7% after exposure to 10、50 µg/ml PM(2.5) and positive control group. The western blot results showed that compared with the control group, c-myc protein increased respectively 29.7%、77.3% after exposure to 50 µg/ml PM(2.5) and positive control group; c-fos protein increased respectively 200.3%、137.0% after exposure to 50 µg/ml PM(2.5) and positive control group; k-ras protein increased respectively 106.3%、130.3%、116.7% after exposure to 10、50 µg/ml PM(2.5) and positive control group; p53 protein decreased by 43.7%、53.3%、52.1% after exposure to 10、50 µg/ml PM(2.5) and positive control group. Conclusion: PM(2.5) could promote the expression of oncogenes in HBE cells, the carcinogenicity of haze might be related to promotion of oncogenes expression induced by PM(2.5).


Assuntos
Células Epiteliais/efeitos dos fármacos , Oncogenes , Material Particulado/toxicidade , Brônquios/citologia , Células Cultivadas , Humanos , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
19.
Int J Nanomedicine ; 14: 6589-6600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496700

RESUMO

Background: The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. Purpose: We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating KRAS mutations. Methods: NPs were synthesized by the desolvation method. The physicochemical properties and stability of NPs were characterized by dynamic light scattering and transmission electron microscopy. Uptake of fluorescently labelled NPs in wild-type and mutant KRAS cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by KRAS-driven macropinocytosis was confirmed by pharmacological inhibition and genetic knockdown. Results: We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of KRA S than monomeric albumin (ie, dissociated form of clinically used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these NPs exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Conclusions: The uptake of albumin nanoparticles is driven by KRAS. This NP-based strategy targeting RAS-driven macropinocytosis is a facile approach toward improved delivery into KRAS-driven cancers.


Assuntos
Espaço Intracelular/metabolismo , Nanopartículas/administração & dosagem , Oncogenes , Pinocitose , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Linhagem Celular Tumoral , Fenômenos Químicos , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Soroalbumina Bovina/metabolismo
20.
Gynecol Oncol ; 155(2): 340-348, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31477279

RESUMO

OBJECTIVE: To determine the involvement of homeobox D9 (HOXD9) in the survival, proliferation, and metastasis of cervical cancer cells through regulating the expression of human papillomavirus (HPV) 16 E6/E7 genes using the P97 promoter. METHODS: One hundred cases of cervical cancer (CC), CC cell lines SKG-I, SKG-II, SKG-IIIa, SKG-IIIb, HeLa, and SiHa, and a human tumor xenograft mouse model were used to examine the roles of HOXD9 in CC. Knockdown experiments employed RNA interference of HOXD9. qPCR, functional assays, western blotting, DNA microarray, and luciferase and ChIP assays were applied for assessments. RESULTS: All CC cell lines expressed HOXD9 mRNA and protein. In uterine CC, HOXD9 gene expression was significantly higher than in normal cervical tissues. A positive correlation of lymphovascular space invasion and lymph node metastasis with high levels of HOXD9 expression was found in patient samples. HOXD9-knockdown cells in the mouse xenograft model only formed small or no tumors. Knockdown of HOXD9 markedly reduced CC cell proliferation, migration and invasion, induced apoptosis, increased P53 protein expression, and suppressed HPV E6/E7 expression by directly binding to the P97 promoter of HPV16 E6/E7 genes. A positive correlation between HOXD9 and HPV16 E6 expression was found in CC patients. CONCLUSIONS: HOXD9 promotes HPV16 E6 and E7 expression by direct binding to the P97 promoter, which enhances proliferation, migration, and metastasis of CCr cells. Our results suggest that HOXD9 could be a prognostic biomarker and potential therapeutic target in CC.


Assuntos
Proteínas de Homeodomínio/fisiologia , Proteínas de Neoplasias/fisiologia , Infecções por Papillomavirus/genética , Regiões Promotoras Genéticas/genética , Neoplasias do Colo do Útero/virologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Papillomavirus Humano 16/genética , Humanos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Proteínas Oncogênicas Virais/metabolismo , Oncogenes , Proteínas E7 de Papillomavirus/metabolismo , Fenótipo , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/genética
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