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1.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
2.
Biopharm Drug Dispos ; 42(7): 338-347, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34138477

RESUMO

This study was intended to delineate the profile of double-negative T cells (DNTs) in NOD.Cg-Prkdcscid Il2rgtm1wj /SzJ mice and cytokines released from DNTs in vivo and in vitro. Total 4 × 107 cells of RC1012 injection per mice were intravenously infused. IFN-γ, TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-10 were measured in vivo and in vitro. A quantitative polymerase chain reaction (PCR) was employed to determine the gene copies of Notch2-NLA per DNT cell from collected organs. Cytokines were significantly increased in vitro (4 h) and in vivo (3 h). DNT cells were distributed into the lung, liver, heart, and kidney earlier, and redistributed to lymphocyte homing spleen and bone marrow, which seemed to frame a two-compartment pharmacokinetics (PK) model but more data are needed to confirm this, and the clearance of DNT cells fell into first-order kinetics.

4.
Front Immunol ; 11: 1933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072067

RESUMO

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs. Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles. Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort (n = 232) and the testing cohort (n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts (P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts. Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Transcriptoma , Idoso , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Microambiente Tumoral
5.
Int J Cancer ; 146(2): 496-509, 2020 01 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.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes Supressores de Tumor/efeitos dos fármacos , Nicotina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Transporte Vesicular/genética , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Humanos , Camundongos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
6.
Oncol Lett ; 18(2): 1049-1056, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423165

RESUMO

The aim of the present study was to investigate the expression of myosin 9 (MYH9) in epithelial ovarian cancer and to explore its correlation with the clinicopathological parameters and prognosis of epithelial ovarian cancer (EOC). A total of 265 cases of paraffin-embedded ovarian cancer tissues and 41 paratumor tissues which had been pathologically confirmed at the Memorial Hospital of Sun Yat-sen University from 2009 to 2017 were included in the present study. MYH9 expression was investigated with immunohistochemistry using a polyclonal antibody specific for MYH9. MYH9 expression is associated with disease progression free and overall survival in epithelial ovarian cancer patients; and the expression of MYH9 is associated with International Federation of Gynecology and Obstetrics stage, lymph node metastasis, intraperitoneal metastasis, survival status (at last follow-up), intraperitoneal recurrence, residual tumor size and ascites with tumor cells. Moreover, in a multivariate model MYH9 overexpression was an independent predictor of poor survival in epithelial ovarian cancer. MYH9 may be a candidate that plays a oncogenic role in epithelial ovarian cancer. MYH9 is a useful independent prognostic marker in epithelial ovarian cancer, and it may provide a candidate target therapy treatment of ovarian cancer in the future.

7.
Cell Death Dis ; 10(4): 305, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944308

RESUMO

The vacuolar protein sorting 33B (VPS33B) was rarely reported in malignant tumors. In this research, we demonstrated that overexpression of VPS33B inhibited proliferation and chemoresistance to fluorouracil (5-FU) in nasopharyngeal carcinoma (NPC) in vivo and in vitro. Mechanistic analysis confirmed that overexpression of VPS33B modulated EGFR/PI3K/AKT/c-Myc/P53 signaling to arrest the cell cycle at G1/S phase. In addition, miR-133a-3p, a tumor-suppressive miRNA, was induced by P53 and directly targeted the EGFR/PI3K/AKT/c-Myc/P53 signaling and thus formed a negative feedback loop. Furthermore, another tumor suppressor, NESG1, interacted with VPS33B by colocalizing in the cytoplasm. The knockdown of NESG1 reversed the inhibitory effects of the overexpression of VPS33B in NPC cells by downregulating the PI3K/AKT/c-Jun-mediated transcription repression. Surprisingly, VPS33B was downregulated in the nicotine-treated and LMP-1-overexpressing NPC cells by targeting PI3K/AKT/c-Jun-mediated signaling. In addition, patients with higher VPS33B expression had a longer overall survival. Our study is the first to demonstrate that VPS33B is negatively regulated by LMP-1 and nicotine and thus suppresses the proliferation of NPC cells by interacting with NESG1 to regulate EGFR/PI3K/AKT/c-Myc/P53/miR-133a-3p signaling in NPC cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Proteínas do Citoesqueleto/metabolismo , Fluoruracila/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Transporte Vesicular/genética
8.
Mol Ther ; 26(4): 1066-1081, 2018 04 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.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/genética , Nicotina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Regiões 3' não Traduzidas , Adulto , Idoso , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Expressão Ectópica do Gene , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cell Death Dis ; 9(2): 78, 2018 01 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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclina D1/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Via de Sinalização Wnt , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/genética , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Metástase Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica
10.
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
11.
Int J Clin Exp Pathol ; 10(12): 11789-11796, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-31966542

RESUMO

The purpose of the present study is to explore the correlation between regulatory associated protein of mTOR (Raptor) and clinicopathologic features in hepatocellular carcinoma (HCC), including patient survival. Immunohistochemistry was used to examine the expression of Raptor in 90 HCC tissues and peritumoral liver tissues. The relationship between tumor Raptor expression and clinicopathologic characteristics was analyzed. Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. The significance of various survival variables was analyzed using multivariate Cox proportional hazards model. We found that Raptor protein was detected in cytoplasmic compartment. Significantly lower Raptor expression was observed in HCC compared to peritumoral liver cells (P=0.048). The tumor expression levels of Raptor significantly inversely correlated with clinical stage (P=0.026). Patients with high Raptor expression had better recurrence-free survival (P=0.010). Further, we observed that Raptor expression was positively associated with recurrence-free survival of HCC patients with tumor capsule (P=0.043) and without portal vein tumor thrombus (P=0.033) classifications. Finally, we found that Raptor was an independent prognostic factor of recurrence-free survival for patients with HCC (P=0.042). To conclude, our results support that decreased cytoplasmic expression of Raptor is a potentially unfavorable factor in the progression and prognosis of HCC.

12.
Acta Biochim Biophys Sin (Shanghai) ; 48(11): 1042-1049, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27733346

RESUMO

miR-203 is a tumor suppressor which participates in the pathogenesis of many tumors including lung adenocarcinoma. However, the role of miR-203 in suppressing chemotherapy resistance to cisplatin (cis-diamminedichloroplatinum; DDP) as well as its molecular mechanism is still to be determined in lung adenocarcinoma. In this study, we found that miR-203 decreased lung cancer cell migration and invasion, and that increased miR-203 expression sensitized lung adenocarcinoma cells to DDP in vitro Furthermore, ZEB2 was found to be a direct target of miR-203, which induces epithelial-mesenchymal transition (EMT) signal. Knock-down of ZEB2 significantly increased DDP chemosensitivity in lung adenocarcinoma. More interestingly, we also demonstrated that ZEB2 could directly bind to E-box of the miR-203 promoter and suppress its expression in lung adenocarcinoma. Our data reveal that miR-203 serves as a negative feedback by directly suppressing the upstream ZEB2 gene, which inhibits EMT signaling and reduces chemoresistance of DDP. Together, these results highlight a feedback loop between miR-203 and ZEB2, which participates in the pathogenesis of lung adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Transição Epitelial-Mesenquimal , Proteínas de Homeodomínio/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Transdução de Sinais , Homeobox 2 de Ligação a E-box com Dedos de Zinco
13.
Oncotarget ; 7(41): 67288-67301, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27589832

RESUMO

miR-203 is a tumor suppressor that is disregulated in numerous malignancies including nasopharyngeal carcinoma (NPC). However, the role of miR-203 in suppressing tumor stemness, chemotherapy resistance as well as its molecular mechanisms are unclear. In this study, we observed that miR-203 suppressed cell migration, invasion, tumor stemness, and chemotherapy resistance to cisplatin (DDP) in vitro and in vivo. miR-203 exerted these effects by targeting ZEB2 and downstream epithelial-mesenchymal transition (EMT) and tumor stemness signals. Interestingly we observed that miR-203 expression was directly suppressed by ZEB2 via targeting its promoter, which significantly reduced cell migration, invasion, tumor stemness, and chemotherapy resistance in NPC cells. Finally, we found that miR-203 was negatively correlated with ZEB2 expression in NPC tissues and tumor spheres. Our data demonstrate a directly negative feedback loop between miR-203 and ZEB2 participating in tumor stemness and chemotherapy resistance, highlighting the therapeutic potential of targeting this signal for NPC chemotherapy.


Assuntos
Carcinoma/patologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/patologia , Células-Tronco Neoplásicas/patologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/biossíntese , Animais , Carcinoma/genética , Carcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Invasividade Neoplásica/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
14.
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
15.
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
16.
Biotechnol Lett ; 38(5): 761-6, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26892224

RESUMO

OBJECTIVE: To determine the glutathione (GSH) content in a human hepatoma cell line (SMMC-7221) treated with xylitol/selenite, providing a part of an investigation of its anti-cancer mechanisms. RESULTS: The nuclei of SMMC-7221 cells were stained with Hoechst 33258 in an apoptosis assay, and their morphology subsequently changed from circular to crescent shape. The calibration curve (r(2) = 0.992) was established, and GSH content markedly decreased after treated with 0.5 and 1 mg xylitol/selenite l(-1) for 12, 36 and 60 h (12 h: from 95.57 ± 19.57 to 29.09 ± 7.74 and 24.27 ± 11.15; 36 h: from 70.73 ± 11.35 to 19.54 ± 6.39 and 9.35 ± 6.69; 60 h: from 72.63 ± 16.94 to 7.432 ± 3.84 and 0). The depletion rate of GSH was more related to the concentration of xylitol/selenite than the treatment time (from 69.95 ± 1.87 to 100 % vs. 0.22 ± 0.2 to 100 %). CONCLUSIONS: Xylitol/selenite is a promising anti-cancer drug to induce apoptosis in SMMC-7221 cells. It may regulate the apoptosis through the co-action of multiple mechanisms related to GSH depletion.


Assuntos
Antineoplásicos/metabolismo , Eletroforese Capilar , Glutationa/análise , Ácido Selenioso/metabolismo , Xilitol/metabolismo , Apoptose , Linhagem Celular Tumoral , Hepatócitos/química , Hepatócitos/efeitos dos fármacos , Humanos
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 35(12): 1765-9, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-26714913

RESUMO

OBJECTIVE: To investigate the expression patterns of ZEB2 and C-myc in epithelial ovarian cancer (EOC) and the associations between their expressions and the pathological features of EOC. METHODS: The expressions of ZEB2 and C-myc proteins were detected immunohistochemically in 191 cervical cancer tissues and 13 normal ovarian tissues. The relationship between ZEB2 and C-myc protein expressions and the clinicopathological features of EOC was evaluated. RESULTS: ZEB2 positive expression ratea in EOC tissues and normal ovarian tissues were 49.2% (94/191) and 30.8% (4/13), respectively (P=0.007), and C-myc positive expression rates in the two tissues were 53.9% (103/191) and 15.4% (2/13), respectively (P=0.001). A high expression of ZEB2 was positively correlated with the pathological type of the tumor (P=0.003), FIGO stage (P=0.028), T stage (P=0.002), and N stage (P=0.04), and a high expression of C-myc was positively correlated with FIGO stage (P=0.035), histological grade (P=0.039), and T stage (P=0.002). C-myc and ZEB2 expressions were positively correlated in EOC (P<0.001), and their co-expression in EOC was significantly correlated with T stage (R=0.358, P<0.001) and FIGO stage (P=0.008). CONCLUSION: ZEB2 and C-myc can promote the progression, invasion and metastasis of EOC, and their combined detection may assist in early diagnosis of EOC.


Assuntos
Progressão da Doença , Proteínas de Homeodomínio/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/metabolismo , Carcinoma Epitelial do Ovário , Feminino , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco
18.
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
19.
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
20.
Biotechnol Lett ; 37(1): 235-40, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25208748

RESUMO

A scaffold provides a framework and initial support for the cells to attach, proliferate and differentiate, and form an extracellular matrix (ECM) in tissue engineering. Here, xyloglucan (XG) was used as a new synthetic ECM for HepG2 cell attachment in alginate capsules. The effects of XG on HepG2 cells on adherent behavior, albumin secretion, ammonia elimination, cell proliferation and gene expression of Connexin 32 and epithelial-cadherin were investigated. Xyloglucan could also promote the HepG2 cell-matrix interactions and the cell clusters formation of HepG2 cells in three dimensional scaffold, thus enhance the liver-specific functions in the three-dimensional space.


Assuntos
Alginatos/química , Glucanos/química , Fígado/metabolismo , Engenharia Tecidual/métodos , Tecidos Suporte/química , Xilanos/química , Alginatos/farmacologia , Amônia/análise , Amônia/metabolismo , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Glucanos/farmacologia , Ácido Glucurônico/química , Ácido Glucurônico/farmacologia , Células Hep G2 , Ácidos Hexurônicos/química , Ácidos Hexurônicos/farmacologia , Humanos , Xilanos/farmacologia
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