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1.
EBioMedicine ; 71: 103558, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34521054

RESUMO

BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. FINDINGS: ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. INTERPRETATION: These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. FUNDING: This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.

3.
Cancer Res ; 81(14): 3835-3848, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049973

RESUMO

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

4.
J Pathol ; 254(3): 265-278, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33797754

RESUMO

Chemoresistance is a major obstacle to the treatment of triple-negative breast cancer (TNBC), which has a poor prognosis. Increasing evidence has demonstrated the essential role of cancer stem cells (CSCs) in the process of TNBC chemoresistance. However, the underlying mechanism remains unclear. In the present study, we report that block of proliferation 1 (BOP1) serves as a key regulator of chemoresistance in TNBC. BOP1 expression was significantly upregulated in chemoresistant TNBC tissues, and high expression of BOP1 correlated with shorter overall survival and relapse-free survival in patients with TNBC. BOP1 overexpression promoted, while BOP1 downregulation inhibited the drug resistance and CSC-like phenotype of TNBC cells in vitro and in vivo. Moreover, BOP1 activated Wnt/ß-catenin signaling by increasing the recruitment of cyclic AMP response element-binding protein (CBP) to ß-catenin, enhancing CBP-mediated acetylation of ß-catenin, and increasing the transcription of downstream stemness-related genes CD133 and ALDH1A1. Notably, treating with the ß-catenin/CBP inhibitor PRI-724 induced an enhancement of chemotherapeutic response of paclitaxel in BOP1-overexpressing TNBC cells. These findings indicate that BOP1 is involved in chemoresistance development and might serve as a prognostic marker and therapeutic target in TNBC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5.
Adv Sci (Weinh) ; 8(4): 2001961, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33643786

RESUMO

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

6.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
7.
EBioMedicine ; 43: 238-252, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31047858

RESUMO

BACKGROUND: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). METHODS: The deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. FINDINGS: NKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. INTERPRETATION: Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.


Assuntos
Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Ácidos Graxos/metabolismo , Proteínas de Homeodomínio/genética , Deleção de Sequência , Fatores de Transcrição/genética , Animais , Biomarcadores , Carcinoma Epitelial do Ovário/mortalidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Camundongos , Modelos Biológicos , Oxirredução , Prognóstico , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Microambiente Tumoral
8.
Clin Cancer Res ; 25(3): 1022-1035, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279231

RESUMO

PURPOSE: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/ß-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/ß-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. RESULTS: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited ß-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/ß-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. CONCLUSIONS: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.


Assuntos
Carcinoma Epitelial do Ovário/genética , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , MicroRNAs/genética , Fragmentos de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Sialoglicoproteínas/genética , Transativadores/genética , beta Catenina/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pirimidinonas/administração & dosagem , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transativadores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Oncogene ; 38(15): 2736-2749, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30542119

RESUMO

Tumor-associated lymphangiogenesis has attracted increasing attention because of its potential contribution to lymph node metastasis. However, the molecular mechanisms underlying lymphangiogenesis in cancer remains elusive. In the current study, we demonstrate that tripartite motif-containing 3 (TRIM3) directly interacts with and induces E3 ligase-dependent proteasomal turnover of importin α3 and α-Actinin-4 (ACTN4), which controls nuclear factor kappa B (NF-κB) activity at a well-ordered level. Heterozygous deletion-mediated TRIM3 downregulation led to NF-κB constitutive activation through disruption of the NF-κB-IκB-α negative feedback loop and enhancement of the p65 DNA-binding affinity and transcriptional activity via promoting symmetrical dimethylarginine modification of NF-κB/p65 at Arg30 and Arg35, which consequently promoted lymphatic metastasis of esophageal squamous cell carcinoma (ESCC) cells. Treatment with Tecfidera, a medication used to treat multiple sclerosis, restored the negative feedback inhibition of NF-κB by reducing the NF-κB/ACTN4 interaction and decreasing symmetrically dimethylated NF-κB levels, resulting in inhibition of ESCC lymphatic metastasis both in vitro and in vivo. Taken together, our results uncover a novel mechanism for constitutive NF-κB activation in cancer and may represent an attractive strategy to treat ESCC lymphatic metastasis.


Assuntos
Proteínas de Transporte/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Linfangiogênese/genética , Metástase Linfática/genética , Metástase Linfática/patologia , Actinina/genética , Linhagem Celular , Neoplasias Esofágicas/patologia , Humanos , Inibidor de NF-kappaB alfa/genética , NF-kappa B/genética , Transdução de Sinais/genética
10.
Theranostics ; 8(18): 5143-5158, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30429891

RESUMO

High levels of angiogenesis are associated with poor prognosis in patients with gliomas. However, the molecular mechanisms underlying tumor angiogenesis remain unclear. Methods: The effect of homeobox C10 (HOXC10) on tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) and on chicken chorioallantoic membranes (CAMs) was examined. An animal xenograft model was used to examine the effect of HOXC10 on xenograft angiogenesis or the effect of bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), on HOXC10-overexpressing xenografts. A chromatin immunoprecipitation assay was applied to investigate the mechanism in which HOXC10 regulated VEGFA expression. Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result. We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors. Mechanistically, HOXC10 could transcriptionally upregulate VEGFA expression by binding to its promoter. Strikingly, treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited the growth of HOXC10-overexpressing tumors and efficiently impaired angiogenesis. Protein arginine methyltransferase 5 (PRMT5) and WD repeat domain 5 (WDR5), both of which regulate histone post-translational modifications, were required for HOXC10-mediated VEGFA upregulation. Importantly, a significant correlation between HOXC10 levels and VEGFA expression was observed in a cohort of human gliomas. Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas.


Assuntos
Glioma/patologia , Proteínas de Homeodomínio/biossíntese , Neovascularização Patológica , Proteína-Arginina N-Metiltransferases/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/biossíntese , Inibidores da Angiogênese/administração & dosagem , Animais , Bevacizumab/administração & dosagem , Movimento Celular , Proliferação de Células , Embrião de Galinha , Membrana Corioalantoide/patologia , Imunoprecipitação da Cromatina , Expressão Gênica , Redes Reguladoras de Genes , Xenoenxertos , Histona-Lisina N-Metiltransferase/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Transplante de Neoplasias , Mapas de Interação de Proteínas
11.
Cancer Res ; 78(22): 6399-6412, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30254148

RESUMO

Blocking genotoxic stress-induced NF-κB activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-κB pathway, the genotoxic agents-induced "nuclear-to-cytoplasmic" NF-κB pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-κB via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-κB activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-κB and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-node-metastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-κB pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-κB activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer.Significance: In response to genotoxic stress, TRIM37 activates NF-κB signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. Cancer Res; 78(22); 6399-412. ©2018 AACR.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Quinase I-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Metástase Linfática , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Mutagênicos , Transplante de Neoplasias , Fosforilação , Transdução de Sinais , Processos Estocásticos , Fator 6 Associado a Receptor de TNF/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
12.
Oncogene ; 37(40): 5476, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30158671

RESUMO

Following the publication of this article the authors noted the affiliation details for corresponding author Dr. Wei Zhang was listed incorrectly. The correct affiliation is Neurosurgical Research Institute, The First Affiliated Hospital of Guangdong Pharmaceutics University, Guangzhou, China.

13.
Theranostics ; 8(13): 3571-3583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026867

RESUMO

It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown. Methods: TFAP4 expression levels in hepatocellular carcinoma (HCC) cells and tissues were detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of TFAP4 in the tumor-initiating cell (TIC)-like phenotype and the tumorigenic capability of HCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of TFAP4-mediated HCC aggressiveness. Results: TFAP4 was markedly upregulated in human HCC, and was associated with significantly poorer overall and relapse-free survival in patients with HCC. Furthermore, we found that overexpression of TFAP4 significantly enhanced, whereas silencing TFAP4 inhibited, the tumor sphere formation ability and proportion of side-population cells in HCC cells in vitro, and ectopic TFAP4 enhanced the tumorigenicity of HCC cells in vivo. Mechanistically, we demonstrated that TFAP4 played an important role in activating Wnt/ß-catenin signaling by directly binding to the promoters of DVL1 (dishevelled segment polarity protein 1) and LEF1 (lymphoid enhancer binding factor 1). Conclusions: Our results provide new insight into the mechanisms underlying hyperactivation of the Wnt/ß-catenin pathway in HCC, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of HCC cells.


Assuntos
Carcinogênese , Carcinoma Hepatocelular/fisiopatologia , Proteínas de Ligação a DNA/metabolismo , Proteínas Desgrenhadas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Carcinoma Hepatocelular/patologia , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica , Genes Reporter , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Luciferases/análise , Regiões Promotoras Genéticas , Ligação Proteica , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
14.
Oncogene ; 37(40): 5403-5415, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29867201

RESUMO

Gliomas are a lethal class of brain cancer, with a median survival below 15 months in spite of therapeutic advances. The poor prognosis of this disease is largely attributed to acquired chemotherapy resistance, and new strategies are urgently needed to target resistant glioma cells. Herein, our study demonstrated that tripartite motif-containing 14 (TRIM14) overexpressed in glioma specimens (including tissues and cell lines), and that high level of TRIM14 predicted poor outcome of glioma patients. Furthermore, we found that upregulation of TRIM14 in glioma cells conferred chemoresistance to temozolomide in vitro and in vivo; conversely, silencing TRIM14 sensitized glioma cells to temozolomide. These findings demonstrated that TRIM14 stabilized dishevelled (Dvl2) and subsequently activated the canonical Wnt signaling and promoted chemoresistance. Moreover, inhibition of Dvl2 reversed the oncogenic effect of TRIM14 on chemoresistance. Importantly, consistent with the abovementioned results, we found that TRIM14 expression was significantly associated with hyperactivation of canonical Wnt pathway in clinical glioma specimens. Collectively, the study reveals a new molecular mechanism driving chemotherapy resistance in gliomas, and suggests an opportunity to develop novel therapeutic interventions against gliomas.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Desgrenhadas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioma/patologia , Via de Sinalização Wnt , Proteínas de Transporte/genética , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Estabilidade Proteica , Análise de Sobrevida , Temozolomida/farmacologia , Proteínas com Motivo Tripartido , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
15.
Mol Carcinog ; 57(9): 1181-1190, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29745440

RESUMO

Gliomas are common, aggressive central nervous system tumors with poor overall survival rates. Despite improvements in neurosurgery, chemotherapy, and radiotherapy, the outcomes of patients with malignant gliomas remain poor. Therefore, increased knowledge of the molecular mechanisms that regulate glioma progression is crucial to identify novel therapeutic targets. Here, we reported that SHCBP1, a member of Src homolog and collagen homolog (Shc) family, was significantly overexpressed in glioma tissues and glioma cell lines compared to the corresponding normal tissues and cells. Ectopic overexpression of SHCBP1 promoted glioma cell migration and invasion, whereas knockdown of endogenous SHCBP1 had the opposite effects. Importantly, we demonstrated that SHCBP1 promoted aggressiveness in gliomas by activating the NF-κB signaling pathway. Collectively, our study indicates that SHCBP1 plays a pivotal role to promote progression in gliomas and targeting the oncogenic effects of SHCBP1 may provide a clinical strategy to treat gliomas.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , NF-kappa B/imunologia , Invasividade Neoplásica/genética , Proteínas Adaptadoras da Sinalização Shc/genética , Regulação para Cima , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Glioma/imunologia , Glioma/patologia , Humanos , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Proteínas Adaptadoras da Sinalização Shc/imunologia , Transdução de Sinais
16.
Mol Cancer ; 16(1): 106, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28633632

RESUMO

BACKGROUND: The plasticity of cancer stem cells (CSCs)/tumor-initiating cells (T-ICs) suggests that multiple CSC/T-IC subpopulations exist within a tumor and that multiple oncogenic pathways collaborate to maintain the CSC/T-IC state. Here, we aimed to identify potential therapeutic targets that concomitantly regulate multiple T-IC subpopulations and CSC/T-IC-associated pathways. METHODS: A chemoresistant patient-derived xenograft (PDX) model of human esophageal squamous cell carcinoma (ESCC) was employed to identify microRNAs that contribute to ESCC aggressiveness. The oncogenic effects of microRNA-455-3p (miR-455-3p) on ESCC chemoresistance and tumorigenesis were examined by in vivo and in vitro chemoresistance, tumorsphere formation, side-population, and in vivo limiting dilution assays. The roles of miR-455-3p in activation of the Wnt/ß-catenin and transforming growth factor-ß (TGF-ß)/Smad pathways were determined by luciferase and RNA immunoprecipitation assays. RESULTS: We found that miR-455-3p played essential roles in ESCC chemoresistance and tumorigenesis. Treatment with a miR-455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/ß-catenin and TGF-ß signaling. Importantly, miR-455-3p exhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients. CONCLUSIONS: Our results demonstrate that miR-455-3p functions as an oncomiR in ESCC progression and may provide a potential therapeutic target to achieve better clinical outcomes in cancer patients.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , MicroRNAs/genética , Animais , Antagomirs/farmacologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 7(17): 24076-87, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-26992223

RESUMO

Constitutive activation of the Wnt/ß-catenin pathway promotes malignant proliferation and it is inversely correlated with the prognosis of patients with breast cancer. However, mutations in key regulators, such as APC, Axin and ß-catenin, contribute to aberrant activation of the Wnt/ß-catenin signaling pathway in various cancers, but rarely found in breast cancer, suggesting that other mechanisms might be involved in the activation of Wnt/ß-catenin signaling in breast cancer. In the present study, we found that miR-1229 expression was markedly upregulated in breast cancer and associated with poor survival. Overexpressing miR-1229 promoted while inhibiting miR-1229 reduced, proliferation of breast cancer cell proliferation in vitro and tumor growth in vivo. Furthermore, we found that overexpression of miR-1229 activated the Wnt/ß-catenin signaling pathway in breast cancer by directly targeting the multiple important negative regulators of Wnt/ß-catenin signaling, including adenomatous polyposis coli (APC), glycogen synthase kinase-3ß (GSK-3ß), and inhibitor of ß-catenin and T cell factor (ICAT). Taken together, our results suggest that miR-1229 plays an important role in promotion breast cancer progression and may represent a novel therapeutic target in breast cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Transformação Celular Neoplásica/patologia , MicroRNAs/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Células Tumorais Cultivadas , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
18.
Sci Rep ; 6: 21549, 2016 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-26899563

RESUMO

Suprabasin is a recently identified oncoprotein that is upregulated in multiple cancers. However, the clinical significance and biological role of suprabasin in human esophageal squamous cell carcinoma (ESCC) remains unclear. In the current study, we reported that suprabasin was markedly overexpressed in ESCC cell lines and tissues at both mRNA and protein levels, and this was associated with advanced clinical stage, tumor-nodes-metastasis (TNM) classification, histological differentiation, tumor size and poorer survival. Furthermore, we found that both proliferation and tumorigenicity of ESCC cells were significantly induced by suprabasin overexpression, but inhibited by suprabasin knock-down. Moreover, we demonstrated that upregulation of suprabasin activated the Wnt/ß-catenin signaling pathway and led to nuclear localization of ß-catenin and upregulation of Cyclin D1 and c-Myc. Together, our results suggest that suprabasin plays an important oncogenic role in promoting proliferation and tumorigenesis of ESCC.


Assuntos
Antígenos de Diferenciação/genética , Carcinoma de Células Escamosas/genética , Ciclina D1/biossíntese , Neoplasias Esofágicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , beta Catenina/biossíntese , Antígenos de Diferenciação/biossíntese , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina D1/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
19.
Cancer Res ; 76(5): 1101-11, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26747895

RESUMO

The strength and duration of NF-κB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-κB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-κB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-κB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy.


Assuntos
Neoplasias da Mama/patologia , MicroRNAs/fisiologia , NF-kappa B/fisiologia , Animais , Neoplasias da Mama/genética , Metilação de DNA , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Poliubiquitina/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais/fisiologia
20.
Oncotarget ; 6(30): 28882-94, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26337084

RESUMO

Wnt/ß-catenin signaling pathway is strictly controlled by multiple negative regulators. However, how tumor cells override the negative regulatory effects to maintain constitutive activation of Wnt/ß-catenin signaling, which is commonly observed in various cancers, remains puzzling. In current study, we reported that overexpression of miR-1207 in ovarian cancer activated Wnt/ß-catenin signaling by directly targeting and suppressing secreted Frizzled-related protein 1 (SFRP1), AXIN2 and inhibitor of ß-catenin and TCF-4 (ICAT), which are vital negative regulators of the Wnt/ß-catenin pathway. We found that the expression of miR-1207 was ubiquitously upregulated in both ovarian cancer tissues and cells, which inversely correlated with patient overall survival. Furthermore, overexpression of miR-1207 enhanced, while silencing miR-1207 reduced, stem cell-like traits of ovarian cancer cells in vitro and in vivo, including tumor sphere formation capability and proportion of SP+ and CD133+ cells. Importantly, upregulating miR-1207 promoted, while silencing miR-1207 inhibited, the tumorigenicity of ovarian cancer cells. Hence, our results suggest that miR-1207 plays a vital role in promoting the cancer stem cell-like phenotype in ovarian cancer and might represent a potential target for anti-ovarian cancer therapy.


Assuntos
MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Antígeno AC133 , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Proteína Axina/genética , Proteína Axina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Peptídeos/genética , Peptídeos/metabolismo , Fenótipo , Fatores de Tempo , Transfecção , Carga Tumoral , Regulação para Cima , Via de Sinalização Wnt/genética , beta Catenina/genética
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