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1.
Int J Cancer ; 146(2): 496-509, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125123

RESUMO

The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) -induced CRC mice models and nicotine-treated CRC cells via the PI3K/AKT/c-Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and the downstream cell cycle or EMT-related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c-Jun-mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B-modulating signal in VPS33B-overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.

2.
Biomed Pharmacother ; 121: 109562, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31707341

RESUMO

BACKGROUND: Lung cancer has been the most common cancer worldwide. Microsomal glutathione S-transferase 1 (MGST1) has been reported to play vital roles in oxidative stress, tumor occurrence and drug resistance. However, the biological function and molecular mechanism of MGST1 in lung adenocarcinoma (LUAD) has not yet been elucidated. METHODS: The expression of MGST1 in LUAD tissues and cell lines was evaluated by immunohistochemistry and western blotting, respectively. MGST1 was knocked down by shRNA lentivirus. Cell proliferation was evaluated by MTS, colony formation and EdU assays. Apoptosis was detected by flow cytometry. The potential molecules involved in cell proliferation and apoptosis were examined by western blotting. Finally, the effect of MGST1 on tumor growth in vivo was evaluated in a nude mouse xenograft model. RESULTS: TCGA database analysis and immunohistochemistry demonstrated that MGST1 was highly expressed in LUAD tissues. MGST1 expression in LUAD was correlated with AJCC stage and poor overall survival of patients. MGST1 knockdown significantly inhibited LUAD cell proliferation and induced apoptosis. Mechanistic analyses revealed that MGST1 knockdown might inhibit cell proliferation by inactivating the AKT/GSK-3ß pathway signaling and promote cell apoptosis by regulating the mitochondrial apoptosis pathway related proteins. Moreover, knockdown of MGST1 suppressed tumor growth in vivo. CONCLUSIONS: MGST1 plays an important role in LUAD tumorigenesis and might serve as a potential prognostic factor and therapeutic target in LUAD.

3.
Bioengineered ; 10(1): 425-436, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31564210

RESUMO

Stromal interaction molecule 1 (STIM1) is a calcium-sensing protein localized in the membrane of the endoplasmic reticulum. The expression of STIM1 has been shown to be closely associated with cell proliferation. The aim of the present study was to investigate the role of STIM1 in the regulation of cancer progression and its clinical relevance. The data demonstrated that the expression of the STIM1 was significantly higher in non-small-cell lung cancer (NSCLC) tissues than in benign lesions and was associated with advanced NSCLC T stage. Knockdown of STIM1 expression in NSCLC cell lines A549 and SK-MES-1 significantly inhibited cell proliferation and induces A549 and SK-MES-1 cell arrest at the G2/M and S phases of the cell cycle. Western blotting showed that the expression of cyclin-dependent kinase (CDK) 1 and CDK2 were reduced while knockdown of STIM1 expression. Furthermore, knockdown of STIM1 in NSCLC cells significantly reduced the levels of xenograft tumor growth in nude mice. These data indicate that aberrant expression of the STIM1 protein may contribute to NSCLC progression. Future studies should focus on targeting STIM1 as a novel strategy for NSCLC therapy.

4.
Oncol Rep ; 42(5): 1843-1855, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432177

RESUMO

Despite the increasing number of available therapeutic methods, the prognosis of non­small cell lung cancer (NSCLC) remains poor. Furthermore, side effects are an important limiting factor in the treatment of NSCLC. Therefore, developing an efficacious, safe, affordable and easily accessible chemotherapeutic agent is necessary for NSCLC treatment. As a natural chemical produced by Zingiberaceae plants, curcumin exerts distinct antitumor effects on several tumor types. In the present study, curcumin was observed to inhibit not only cell proliferation and cell cycle transition, but also cell migration in NSCLC, as determined by a series of experiments (such as MTS assay, colony formation assay, flow cytometric analysis, Transwell migration assay and western blotting). Mechanistically, curcumin induced G2/M phase arrest by controlling cell cycle­ and epithelial­mesenchymal transition (EMT)­related checkpoints. Furthermore, curcumin significantly inhibited the expression of Toll­like receptor 4 (TLR4)/MyD88 and EGFR in a dose­ and time­dependent manner. Conversely, EGF reversed the inhibitory action of curcumin on TLR4/MyD88. In clinical specimens, TLR4 and MyD88 were highly expressed in NSCLC tissues, and a significant positive association was observed between TLR4 and MyD88 expression. These data suggested that curcumin may control the EGFR and TLR4/MyD88 pathways to synergistically downregulate downstream cell cycle­ and EMT­related regulators, in order to block cell proliferation and metastasis in NSCLC. These findings provide evidence for the clinical application of curcumin.

5.
Genome Biol ; 20(1): 103, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126313

RESUMO

BACKGROUND: Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo. RESULTS: We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer. CONCLUSION: This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress.


Assuntos
Cromossomos Humanos Par 13 , Elementos Facilitadores Genéticos , Neoplasias Pulmonares/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Linhagem Celular Tumoral , Reparo do DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Humanos , Desequilíbrio de Ligação , Neoplasias Pulmonares/metabolismo , Polimorfismo de Nucleotídeo Único
6.
Oncol Rep ; 41(4): 2337-2350, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720128

RESUMO

Src homology 2­containing inositol­5'­phosphatase 1 (SHIP1) serves a vital role in the occurrence and development of hematological tumors, but there is limited knowledge regarding the role of SHIP1 in various solid tumors, including lung cancer. In the present study, the aim was to investigate the expression and functional mechanisms of SHIP1 in non­small cell lung cancer (NSCLC). The Gene Expression Omnibus database demonstrated that SHIP1 had low expression in NSCLC. Further studies using fresh tissues and cell lines also confirmed this observation. Biological function analyses revealed that SHIP1 overexpression notably suppressed cell growth, migration and invasion in vitro and in vivo in NSCLC. Mechanistic analyses indicated that SHIP1 inactivated the phosphoinositide 3­kinase (PI3K)/AKT pathway to suppress signals associated with the cell cycle and epithelial­mesenchymal transition. In clinical specimens, reduced SHIP1 is an unfavorable factor and is negatively associated with the T classification, N classification and clinical stage. Furthermore, patients with low SHIP1 levels exhibited reduced survival rate, compared with patients with high levels of the protein. Notably, the promoter of the SHIP1 gene lacks CpG islands, and the suppression of SHIP1 expression is not associated with epidermal growth factor receptor or Kirsten rat sarcoma mutations. Thus, the present study demonstrated that SHIP1 inhibits cell growth, migration and invasion in NSCLC through the PI3K/AKT pathway. Additionally, reduced SHIP1 expression may be an unfavorable factor for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Ther ; 26(4): 1066-1081, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29525743

RESUMO

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.

8.
Cell Death Dis ; 9(2): 78, 2018 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362431

RESUMO

MiR-374a appears to play a complex role in non-small-cell lung cancer (NSCLC). Here, we demonstrate a dual role for miR-374a in NSCLC pathogenesis. The effects and modulatory mechanisms of miR-374a on cell growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed. The expression of miR-374a was examined in NSCLC and non-cancerous lung tissues by quantitative real-time reverse transcription-PCR (qRT-PCR), and in situ hybridization, respectively. miR-374a directly targets CCND1 and inactivates PI3K/AKT and Ras-mediated cell cycle signalings, as well as epithelial-mesenchymal transition (EMT). This not only dramatically suppressed cell growth, migration, invasion,and metastasis, but also elevated A549 and pc-9 NSCLC cell sensitivity to cisplatin (DDP) while increasing survival time of tumor-bearing mice. Interestingly, miR-374a serves an inverse function in SPCA-1 and H1975 NSCLC cells by directly targeting PTEN to activate Wnt/ß-catenin and Ras signalings and its downstream cascade signals. Surprisingly, transcription factor c-Jun bound to the promoter region of human miR-374a and suppressed miR-374a in A549 and pc-9 cells while inducing it in SPCA-1 and H1975 cells. Increased levels of miR-374a appeared to serve a protective role by targeting CCND1 in early-stage NSCLC (Stages I and II). Inversely, increased miR-374a was an unfavorable factor when targeting PTEN in more advanced staged NSCLC patients. Our studies are the first to demonstrate that miR-374a plays divergent roles in NSCLC pathogenesis at different stages of the disease and implicate the potential application of miR-374a targeting for cancer therapy.

9.
Clin Cancer Res ; 23(20): 6336-6350, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28751441

RESUMO

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA-protein complex and HDGF/DDX5/ß-catenin complex.Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK-Ras-c-Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF-ß-catenin-c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA-FAK-Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces ß-catenin-c-Myc, which suppresses miR-296-3p and further activates PRKCA-FAK-Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.Conclusions: Our study provides a novel mechanism that the miR-296-3p-PRKCA-FAK-Ras-c-Myc feedback loop modulated by HDGF/DDX5/ß-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336-50. ©2017 AACR.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Proteoma , Transcriptoma , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Proliferação de Células , RNA Helicases DEAD-box/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Complexos Multiproteicos , Metástase Neoplásica , Regiões Promotoras Genéticas , Ligação Proteica , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , beta Catenina/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
10.
Oncotarget ; 7(27): 41306-41319, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27191497

RESUMO

microRNA-374a (miR-374a) exhibits oncogenic functions in various tumor types. Here we report that miR-374a suppresses proliferation, invasion, migration and intrahepatic metastasis in colon adenocarcinoma cell lines HCT116 and SW620. Notably, we detected that PI3K/AKT signaling and its downstream cell cycle factors including c-Myc, cyclin D1 (CCND1), CDK4 and epithelial-mesenchymal transition (EMT)-related genes including ZEB1, N-cadherin, Vimentin, Slug, and Snail were all significantly downregulated after miR-374a overexpression. Conversely, cell cycle inhibitors p21 and p27 were upregulated. Expression of E-cadherin was only decreased in HCT116, without any obvious differences observed in SW620 cells. Furthermore, luciferase reporter assays confirmed that miR-374a could directly reduce CCND1. Interestingly, when CCND1 was silenced or overexpressed, levels of pPI3K, pAkt as well as cell cycle and EMT genes were respectively downregulated or upregulated. We examined miR-374a levels by in situ hybridization and its correlation with CCND1 expression in CRC tumor tissues. High miR-374a expression with low level of CCND1 was protective factor in CRC. Together these findings indicate that miR-374a inactivates the PI3K/AKT axis by inhibiting CCND1, suppressing of colon cancer progression.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Ciclina D1/genética , Genes Supressores de Tumor , MicroRNAs/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética
11.
Nat Commun ; 7: 11309, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27095304

RESUMO

The biological role of miR-3188 has not yet been reported in the context of cancer. In this study, we observe that miR-3188 not only reduces cell-cycle transition and proliferation, but also significantly prolongs the survival time of tumour-bearing mice as well as sensitizes cells to 5-FU. Mechanistic analyses indicate that miR-3188 directly targets mTOR to inactivate p-PI3K/p-AKT/c-JUN and induces its own expression. This feedback loop further suppresses cell-cycle signalling through the p-PI3K/p-AKT/p-mTOR pathway. Interestingly, we also observe that miR-3188 direct targeting of mTOR is mediated by FOXO1 suppression of p-PI3K/p-AKT/c-JUN signalling. In clinical samples, reduced miR-3188 is an unfavourable factor and negatively correlates with mTOR and c-JUN levels but positively correlates with FOXO1 expression. Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and NPC chemotherapy resistance.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fosfatidilinositol 3-Quinases/genética , Serina-Treonina Quinases TOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo
12.
Oncotarget ; 6(17): 15610-27, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-25951350

RESUMO

ENO1 plays a paradoxical role in driving the pathogenesis of tumors. However, the clinical significance of ENO1 expression remains unclear and its function and modulatory mechanisms have never been reported in endometrial carcinoma (EC). In this study, ENO1 silencing significantly reduced cell glycolysis, proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by modulating p85 suppression. This in turn mediated inactivation of PI3K/AKT signaling and its downstream signals including glycolysis, cell cycle progression, and epithelial-mesenchymal transition (EMT)-associated genes. These effects on glycolysis and cell growth were not observed after ENO1 suppression in normal human endometrial epithelial cells (HEEC). Knocking down ENO1 could significantly enhance the sensitivity of EC cells to cisplatin (DDP) and markedly inhibited the growth of EC xenografts in vivo. In clinical samples, EC tissues exhibited higher expression levels of ENO1 mRNA and protein compared with normal endometrium tissues. Patients with higher ENO1 expression had a markedly shorter overall survival than patients with low ENO1 expression. We conclude that ENO1 favors carcinogenesis, representing a potential target for gene-based therapy.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/patologia , Fosfopiruvato Hidratase/genética , Proteínas Supressoras de Tumor/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Neoplasias do Endométrio/mortalidade , Endométrio/patologia , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Transdução de Sinais/genética , Transplante Heterólogo
13.
J Hematol Oncol ; 8: 22, 2015 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-25887760

RESUMO

BACKGROUND: During tumor formation and expansion, increasing glucose metabolism is necessary for unrestricted growth of tumor cells. Expression of key glycolytic enzyme alpha-enolase (ENO1) is controversial and its modulatory mechanisms are still unclear in non-small cell lung cancer (NSCLC). METHODS: The expression of ENO1 was examined in NSCLC and non-cancerous lung tissues, NSCLC cell lines, and immortalized human bronchial epithelial cell (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR), immunohistochemistry, and Western blot, respectively. The effects and modulatory mechanisms of ENO1 on cell glycolysis, growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed. RESULTS: ENO1 expression was increased in NSCLC tissues in comparison to non-cancerous lung tissues. Similarly, NSCLC cell lines A549 and SPCA-1 also express higher ENO1 than HBE cell line in both mRNA and protein levels. Overexpressed ENO1 significantly elevated NSCLC cell glycolysis, proliferation, clone formation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by regulating the expression of glycolysis, cell cycle, and epithelial-mesenchymal transition (EMT)-associated genes. Conversely, ENO1 knockdown reversed these effects. More importantly, our further study revealed that stably upregulated ENO1 activated FAK/PI3K/AKT and its downstream signals to regulate the glycolysis, cell cycle, and EMT-associated genes. CONCLUSION: This study showed that ENO1 is responsible for NSCLC proliferation and metastasis; thus, ENO1 might serve as a potential molecular therapeutic target for NSCLC treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ligação a DNA/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Fosfopiruvato Hidratase/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Glicólise/fisiologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Transfecção
14.
Dis Markers ; 2014: 298795, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24692842

RESUMO

AIMS: This study examined the correlation between high nuclear expression of hepatoma-derived growth factor (HDGF) and clinicopathologic data in endometrial carcinoma (EC), including patient survival. METHODS: One hundred and twenty-two endometrial carcinoma (EC) patients from 2002 to 2008 were reviewed in the study. HDGF expression in tumor tissues was examined using immunohistochemistry (IHC), and its association with clinicopathological parameters was evaluated. Tumors with 80% or more nuclei staining were regarded as high expression and tumors with less than 80% nuclei staining considered as low expression. RESULTS AND CONCLUSIONS: Immunohistochemical analysis revealed that HDGF was expressed in both the nucleus and cytoplasm. High nuclear expression of HDGF was positively correlated with FIGO stage (P = 0.032), but not associated with other clinical features, such as histological grading or lymph node status. Patients with high expression of HDGF had poorer overall survival rates than those with low expression of HDGF (P = 0.001). However, multivariate analyses showed that high nuclear expression of HDGF protein was not an independent predictor of prognosis for EC patients (P = 0.111). Our results suggest that high nuclear expression of HDGF is a potential unfavorable factor for the progression and prognosis of EC.


Assuntos
Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/mortalidade , Carcinoma/secundário , Núcleo Celular , Progressão da Doença , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
15.
PLoS One ; 8(6): e64976, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23755163

RESUMO

BACKGROUND: The role of CTGF varies in different types of cancer. The purpose of this study is to investigate the involvement of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: CTGF expression levels were examined in NPC tissues and cells, nasopharynx (NP) tissues, and NP69 cells. The effects and molecular mechanisms of CTGF expression on cell proliferation, migration, invasion, and cell cycle were also explored. RESULTS: NPC cells exhibited decreased mRNA expression of CTGF compared to immortalized human nasopharyngeal epithelial cell line NP69. Similarly, CTGF was observed to be downregulated in NPC compared to normal tissues at mRNA and protein levels. Furthermore, reduced CTGF was negatively associated with the progression of NPC. Knocking down CTGF expression enhanced the colony formation, cell migration, invasion, and G1/S cell cycle transition. Mechanistic analysis revealed that CTGF suppression activated FAK/PI3K/AKT and its downstream signals regulating the cell cycle, epithelial-mesenchymal transition (EMT) and MMPs. Finally, DNA methylation microarray revealed a lack of hypermethylation at the CTGF promoter, suggesting other mechanisms are associated with suppression of CTGF in NPC. CONCLUSION: Our study demonstrates that reduced expression of CTGF promoted cell proliferation, migration, invasion and cell cycle progression through FAK/PI3K/AKT, EMT and MMP pathways in NPC.


Assuntos
Movimento Celular/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Carcinoma , Linhagem Celular Tumoral , Proliferação de Células , Células Clonais , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Metilação de DNA/genética , Progressão da Doença , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Epitélio/metabolismo , Epitélio/patologia , Fase G1 , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Carcinoma Nasofaríngeo , Nasofaringe/patologia , Invasividade Neoplásica , Prognóstico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Regiões Promotoras Genéticas/genética , Fase S , Transdução de Sinais/genética
16.
Cell Death Dis ; 4: e872, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24157866

RESUMO

Programmed cell death 4 (PDCD4), a novel tumor suppressor, inhibits cell proliferation, migration and invasion as well as promotes cell apoptosis in tumors. However, the molecular mechanism of its tumor-suppressive function remains largely unknown in tumors including nasopharyngeal carcinoma (NPC). In this study, downregulated PDCD4 expression was significantly associated with the status of NPC progression and poor prognosis. PDCD4 markedly suppressed the ability of cell proliferation and cell survival by modulating C-MYC-controlled cell cycle and BCL-2-mediated mitochondrion apoptosis resistance signals, and oncogenic transcription factor C-JUN in NPC. Furthermore, miR-184, a tumor-suppressive miRNA modulated by PDCD4 directly targeting BCL2 and C-MYC, participated in PDCD4-mediated suppression of cell proliferation and survival in NPC. Further, we found that PDCD4 decreased the binding of C-Jun to the AP-1 element on the miR-184 promoter regions by PI3K/AKT/JNK/C-Jun pathway and stimulated miR-184 expression. In clinical fresh specimens, reduced PDCD4 mRNA level was positively correlated with miR-184 expression in NPC. Our studies are the first to demonstrate that PDCD4 as tumor suppressor regulated miR-184-mediated direct targeting of BCL2 and C-MYC via PI3K/AKT and JNK/C-Jun pathway attenuating cell proliferation and survival in NPC.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , MicroRNAs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Carcinoma , Ciclo Celular/genética , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Adulto Jovem
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