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1.
Am J Cancer Res ; 12(8): 3799-3810, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119811

RESUMO

Genomic instability is a key cancer indicator. It results from defects in the DNA damage response (DDR) and increased replication stress. Herein, we examined how ataxia-telangiectasia mutated interactor (ATMIN), a DDR pathway involved in mismatch repair-proficient (microsatellite stability [MSS]), acts in colorectal carcinoma (CRC). Firstly, ATMIN mRNA expression was detected in CRC specimens with MSS characteristics, and the effects of ectopic ATMIN expression and ATMIN knockdown on invasion abilities were gauged in MSS cell lines. To understand the molecular mechanism, co-immunoprecipitation analyses in vitro were employed. Interestingly, ATMIN expression was positively correlated with advanced stages (P < .001), lymph node metastases (P = .002), and deeper invasion (P = .037) in MSS tumors; and significantly changed the cell motility in vitro. In the high-throughput analysis, ATMIN was found to act on the Wnt signaling pathway via PARP1. PAPR1 inhibition, in turn, significantly decreased invasion abilities resulting from ATMIN overexpression in cancer cell. Taken together, ATMIN, which alters the Wnt signaling pathway regulating CRC progression, plays as a crucial prognostic factor in MSS tumors.

3.
Ann Surg Oncol ; 28(13): 8544-8554, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34148137

RESUMO

BACKGROUND: Constant DNA damage occurs in cells, and the cells are programmed to respond constitutively. This study explored the roles of ataxia-telangiectasia mutated interactor (ATMIN), one of the impaired pathways involving the DNA damage response (DDR) in mismatch repair-deficient [microsatellite instability (MSI)-high] colorectal carcinoma (CRC). METHODS: Expression of ATMIN messenger RNA (mRNA) was detected in CRC specimens with microsatellite instability (MSI) characteristics. The effects of ectopic ATMIN expression and ATMIN knockdown on invasion abilities were evaluated in MSI-high cell lines, and liver metastasis ability was investigated in vivo. Protein-protein interactions were assessed by coimmunoprecipitation analyses in vitro. RESULTS: Decreased ATMIN expression was positively correlated with advanced stage of disease (P < 0.05), lymph node metastases (P < 0.05), and deeper invasion (P < 0.05) in MSI-high tumors. Transient or stable ATMIN knockdown significantly increased cell motility. Moreover, in the high-throughput microarray and gene set enrichment analysis, ATMIN was shown to act on the Wnt-signaling pathway via PARP1. This cascade influences ß-catenin/transcription factor 4 (TCF4) binding affinity in MSI-high tumors, and PARP1 inhibition significantly decreased the number of metastases from ATMIN knockdown cancer cells. CONCLUSIONS: The results not only indicated the critical role of ATMIN, but also shed new light on PARP1 inhibitors, providing a basis for further clinical trials of MSI-high CRC.


Assuntos
Ataxia Telangiectasia , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Colorretais/genética , Humanos , Instabilidade de Microssatélites , Poli(ADP-Ribose) Polimerase-1/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt
4.
J Clin Med ; 9(2)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973037

RESUMO

Background: Metastasis is a severe problem in patients with oral squamous cell carcinoma (OSCC), which is the fifth most common cancer worldwide. Leukemia inhibitory factor (LIF) has been studied in different cancers, while the role of LIF in OSCC remains unclear. Methods: LIF expression was detected in 100 OSCC samples by immunohistochemistry. Effects of LIF on cell motility were evaluated in OSCC cell lines. High-throughput microarray analysis was also conducted. The correlation between LIF and the downstream effector was analyzed by real-time quantitative reverse transcription PCR. Results: Patients with OSCC who had lymph node metastasis or advanced cancer stages showed high LIF expression. OSCC patients with higher LIF expression, advanced stage, large tumor size, or lymph node metastasis had significantly shorter overall survival. LIF regulated cancer cell motilities through outside-in signaling. The inhibin beta A subunit (INHBA) gene was identified as a crucial downstream effector of LIF-promoted OSCC progression and restored migration and invasion abilities in LIF knockdown transfectants. Conclusion: LIF enhances regional lymphatic spread, thus leading to an advanced cancer stage. Regulation of LIF downstream molecules such as INHBA inhibits the invasion or migration ability of cancer cells. Thus, LIF can be a potential target in preventing cancer metastasis and spread.

5.
J Formos Med Assoc ; 117(3): 212-219, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28438434

RESUMO

BACKGROUND/PURPOSE: Deregulation of metabolic pathways is one of the hallmarks of cancer progression. Connective tissue growth factor (CTGF/CCN2) acts as a tumor suppressor in oral squamous cell carcinoma (OSCC). However, the role of CTGF in modulating cancer metabolism is still unclear. METHODS: OSCC cells stably overexpressing CTGF (SAS/CTGF) and shRNA against CTGF (TW2.6/shCTGF) were established. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were examined by the Seahorse XF24 analyzer. The expression of CTGF and mitochondrial biogenesis related genes was measured by real-time polymerase chain reaction or Western blot analysis. RESULTS: CTGF decreased OCR, ECAR, adenosine triphosphate (ATP) generation, mitochondrial DNA (mtDNA), and mitochondrial transcription factor A (mtTFA) protein expression in OSCC cells. Overexpression of mtTFA restored CTGF-decreased OCR, ECAR, mtDNA copy number, migration and invasion of SAS/CTGF cells. Immunoprecipitation assay showed a higher level of ubiquitinated mtTFA protein after CTGF treatment. MG132, an inhibitor of proteasomal degradation, reversed the effect of CTGF on mtTFA protein expression in SAS cells. CONCLUSION: CTGF can decrease glycolysis, mitochondrial oxidative phosphorylation, ATP generation, and mtDNA copy number by increasing mtTFA protein degradation through ubiquitin proteasome pathway and in turn reduces migration and invasion of OSCC cells. Therefore, CTGF may be developed as a potential additive therapeutic drug for oral cancer in the near future.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator de Crescimento do Tecido Conjuntivo/fisiologia , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias Bucais/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina/fisiologia , Linhagem Celular Tumoral , Humanos
7.
Oral Oncol ; 66: 100-107, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28012797

RESUMO

OBJECTIVES: Relapse is the most serious problem affecting the morbidity and mortality rates of patients with head and neck squamous cell carcinoma (HNSCC). Although HNSCC has been studied for several decades, the exact mechanism of cancer recurrence remains unclear. MATERIALS AND METHODS: ataxia-telangiectasia mutated interactor (ATMIN) messenger RNA(mRNA) expression was detected in HNSCC samples by quantitative RT-PCR, and was analyzed with patients' clinical outcomes by Kaplan-Meier analyses. The ectopic ATMIN expression or ATMIN silencing on invasion ability was evaluated in HNSCC cell lines. Lymph node metastasis ability was investigated by buccal orthotopic implantation in vivo. All statistical tests were two-sided. RESULTS: ATMIN mRNA expression was positively correlated with patients' clinical outcomes. ATMIN blockage reduced invasion, migration, and metastasis abilities both in vitro and in vivo. Evidence from a buccal orthotopic implantation mice model showed that silenced ATMIN expression prolongs mice survival and reduced lymph node metastasis. In high-throughput microarray and bioinformative analyses, KRas was identified as a crucial downstream effector in ATMIN-mediated HNSCC metastasis and was positively associated with patients' clinical stages and ATMIN mRNA expression. CONCLUSIONS: The role of ATMIN and its regulatory mechanisms in HNSCC progression are reported for the first time. The study results improve our understanding of the ATMIN-KRas axis leading to HNSCC migration or invasion and metastasis and facilitates the identification of possible therapy targets of downstream genes for designing effective therapeutic strategies in personalized medicine.


Assuntos
Carcinoma de Células Escamosas/patologia , Genes ras , Neoplasias de Cabeça e Pescoço/patologia , Metástase Linfática/genética , Fatores de Transcrição/fisiologia , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Transcrição/genética
8.
Oncotarget ; 8(14): 22460-22476, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27816970

RESUMO

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) is the rate-limiting enzyme of ketogenesis. Growing evidence indicates that HMGCS2 may be involved in cancer progression, but its exact role is largely unknown. In this study, we demonstrate that HMGCS2 mRNA expression is associated with poor clinical prognosis and outcomes in patients with colorectal cancer (CRC) and oral squamous cell carcinoma (OSCC). In vitro, ectopic expression of HMGCS2 enhanced cancer cell motility in a ketogenesis-independent manner. Moreover, HMGCS2 promoted Src activity by directly binding to peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional activator of Src. Taken together, these results suggest that HMGCS2 may serve as a useful prognostic marker and vital target for future therapeutic strategies against advanced cancer.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Colorretais/metabolismo , Hidroximetilglutaril-CoA Sintase/metabolismo , Mitocôndrias/fisiologia , Neoplasias Bucais/metabolismo , Animais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Movimento Celular , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Camundongos , Camundongos SCID , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/mortalidade , PPAR alfa/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , RNA Interferente Pequeno/genética , Análise de Sobrevida , Células Tumorais Cultivadas
9.
Methods Mol Biol ; 1489: 487-493, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27734399

RESUMO

CCN family members are involved in many physiologic and pathological functions, and be detected in many different cancer types. Immunohistochemistry (IHC) is an important diagnostic pathology tool to demonstrate protein expression in clinical and research fields. Here, we explain the preparation of sample slides, staining procedure, and the problems that might be met during the time. The differential staining of CCN proteins is shown in breast cancer, oral cancer, lung cancer, colorectal cancer, and gastric cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Sinalização Intercelular CCN/metabolismo , Imuno-Histoquímica , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Sinalização Intercelular CCN/genética , Proteína Rica em Cisteína 61/metabolismo , Humanos
10.
Head Neck ; 38 Suppl 1: E1075-85, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26565993

RESUMO

BACKGROUND: Glycolysis machinery regulates cancer cell behavior. However, the roles of these glycolysis enzymes in oral squamous cell carcinoma (OSCC) progression remain unknown. METHODS: Fructose-bisphosphate aldolase C (ALDOC) expression in OSCC patients and cell lines was detected using quantitative real-time polymerase chain reaction (PCR). The functions of ALDOC in migration and invasion were determined using gain and loss of function approaches. An orthotopic OSCC animal model was performed to investigate the effects of ALDOC on metastasis and tumorigenesis in vivo. RESULTS: ALDOC expression is negatively significantly correlated with clinical outcome and cell migration in vitro and in vivo. ALDOC blocks adenosine triphosphate generation and lactate production, and mutation constructs of Arg42 and Lys146 functionally restore ALDOC-inhibited cell migration and invasion. CONCLUSION: ALDOC functions as an OSCC prognosis marker clinically, and suppresses migration and invasion by its catalytic domain of Arg42 and Lys146. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1075-E1085, 2016.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Frutose-Bifosfato Aldolase/metabolismo , Neoplasias Bucais/enzimologia , Animais , Carcinoma de Células Escamosas/diagnóstico , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Mutação , Invasividade Neoplásica , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real
11.
Ann Surg Oncol ; 22(13): 4335-43, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25820997

RESUMO

BACKGROUND: To assess the correlations and functions of complement C1r/C1s, Uegf, Bmp1 domain-containing protein-1 (CDCP1) in identifying colorectal cancer (CRC) patients who are at high risk for metastasis. METHODS: Tumor specimens from 101 patients were analyzed by real-time polymerase chain reaction to detect CDCP1 expression. CDCP1 expression plasmids and shRNA were used to knock down CDCP1 expression in this study to investigate migratory and invasive abilities by Boyden chambers. The mRNA expression profiles in shCDCP1 transfectants were compared to those in control cells by conducting microarray analysis. Its downstream effectors were also invested in this study. RESULTS: CRC patients with a high CDCP1 expression had a statistically significant lower overall survival and disease-free survival compared to those exhibiting low CDCP1 expression. In vitro, knock-down CDCP1 expression significantly decreased migratory and invasive abilities in HCT116. Aberrant expression of CDCP1 increased cancer cell migration and invasion. By using integrated genomics, we identified ROCK1 (rho-associated, coiled-coil-containing protein kinase 1 pseudogene 1) as a downstream effector in CDCP1-mediated migration and as an invasion mediator. Clinically, ROCK1 and CDCP1 mRNA expression exhibited a strong positive correlation in CRC patient samples. CONCLUSIONS: Our results implicated CDCP1 as a key regulator of CRC migration and invasion, and suggest that it is a useful prognostic factor for patients with CRC. Improved identification of a high-risk subset of early metastatic patients may guide indications of individualized treatment in clinical practice.


Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Movimento Celular , Neoplasias Colorretais/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/patologia , Idoso , Antígenos de Neoplasias , Adesão Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas
12.
Oral Oncol ; 51(2): 170-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25435433

RESUMO

OBJECTIVES: MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. MATERIALS AND METHODS: We triggered miR-29b expression in OSCC patients and cell lines by conducting real-time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. RESULTS: The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell-cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression. CONCLUSION: MiR-29b acts as an oncomir, promoting cell migration through CX3CL1 suppression, and could be a potential therapeutic target for preventing OSCC progression.


Assuntos
Carcinoma de Células Escamosas/patologia , MicroRNAs/fisiologia , Neoplasias Bucais/patologia , Metástase Neoplásica , Animais , Quimiocina CX3CL1/genética , Inativação Gênica , Humanos , Metástase Linfática , Camundongos , MicroRNAs/genética , Análise de Sobrevida
13.
Oral Oncol ; 49(9): 923-931, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23602254

RESUMO

OBJECTIVES: Oral squamous cell carcinoma (OSCC) accounts for>90% oral cancer which is a leading cause of cancer death worldwide. Early diagnosis may well offer an opportunity to increase survival to this neoplasm. Micro(mi)RNA-interfered cancer progression is crucial, yet its migration machinery of OSCC is still unknown. To access whether the possible miRNA prognostic markers and underlying mechanisms, we developed a highly migratory TW2.6 MS-10 cells from TW2.6 cells to investigate the issue. MATERIALS AND METHODS: miRNA profiling was performed on TW2.6 and TW2.6 MS-10. Target miRNA was correlated to pathological status in OSCC patients by real-time RT-PCR. A downstream effector was identified using a bioinformatics analysis, and a 3'-untranslated region (UTR) reporter assay was used. RESULTS: An miRNA cluster, miR-17-92, including miR-17, miR-19b, miR-20a, and miR-92a, was found to be significantly down-regulated in TW2.6 MS-10 compared to TW2.6 cells. Overexpression of this cluster decreased the migratory ability of OSCC cell lines. We further demonstrated that miR-17 and miR-20a are the main miRNAs of miR-17-92 cluster which modulate OSCC migration. Clinically, miR-17/20a showed negative correlation with TNM stage and lymphatic metastasis. Through a bioinformatics screening analysis and 3'UTR reporter assay, we confirmed the integrin (ITG) ß8 as a direct target of miR-17/20a, and knockdown of ITGß8 reduced cell migratory capability of OSCC. CONCLUSIONS: miR-17/20a acts as a prognostic predictor of OSCC patients' outcome and a tumor migration suppressor miRNA.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular , MicroRNAs/fisiologia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Humanos , Neoplasias Bucais/genética , Prognóstico
14.
Lab Invest ; 93(4): 480-97, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23399853

RESUMO

Quantitative Image Analysis (QIA) of digitized whole slide images for morphometric parameters and immunohistochemistry of breast cancer antigens was used to evaluate the technical reproducibility, biological variability, and intratumoral heterogeneity in three transplantable mouse mammary tumor models of human breast cancer. The relative preservation of structure and immunogenicity of the three mouse models and three human breast cancers was also compared when fixed with representatives of four distinct classes of fixatives. The three mouse mammary tumor cell models were an ER+/PR+ model (SSM2), a Her2+ model (NDL), and a triple negative model (MET1). The four breast cancer antigens were ER, PR, Her2, and Ki67. The fixatives included examples of (1) strong cross-linkers, (2) weak cross-linkers, (3) coagulants, and (4) combination fixatives. Each parameter was quantitatively analyzed using modified Aperio Technologies ImageScope algorithms. Careful pre-analytical adjustments to the algorithms were required to provide accurate results. The QIA permitted rigorous statistical analysis of results and grading by rank order. The analyses suggested excellent technical reproducibility and confirmed biological heterogeneity within each tumor. The strong cross-linker fixatives, such as formalin, consistently ranked higher than weak cross-linker, coagulant and combination fixatives in both the morphometric and immunohistochemical parameters.


Assuntos
Variação Antigênica/efeitos dos fármacos , Biomarcadores Tumorais/análise , Fixadores/farmacologia , Neoplasias Mamárias Experimentais/patologia , Manejo de Espécimes/normas , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Camundongos , Camundongos da Linhagem 129 , Reprodutibilidade dos Testes
15.
Ann Surg Oncol ; 19 Suppl 3: S385-94, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21681381

RESUMO

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression. METHODS: To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays. RESULTS: CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK-mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples. CONCLUSIONS: Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Recidiva Local de Neoplasia/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Fatores de Necrose Tumoral/metabolismo , Idoso , Neoplasias Colorretais/genética , Citocina TWEAK , Intervalo Livre de Doença , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Técnicas de Inativação de Genes , Células HCT116 , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Proteína de Ligação a Fosfatidiletanolamina/genética , Plasmídeos , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Transfecção , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
J Oral Pathol Med ; 40(7): 567-75, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21332579

RESUMO

BACKGROUND: Histone deacetylase 2 (HDAC2) expressions in oral squamous cell carcinoma (OSCC) had been implicated in advanced stage and poor prognosis. It suggests a possible link between the migration/invasion potential of oral cancer cells and the prevalent expression of HDAC2. METHODS: Five head and neck cancer (HNC) cell lines, including Ca9-22, Cal-27, HSC-3, SAS, and TW2.6, were used. Cells stably overexpressing HDAC2 and shRNA against HDAC2 were established to investigate migration/invasion ability in vitro and tumorigenesis and progression in vivo. RESULTS: We found that alterations in the HDAC2 level in OSCC cell lines modulated their invasive ability with a positive correlation. Animal model also showed that knockdown of HDAC2 expression in SAS cells, originally containing high endogenous HDAC2 expression, resulted in decrease in tumor initiation and progression. Using high-throughput transcriptome analysis, numerous genes involved in HIF-1α-associated pathways were found. At the mechanism levels, using agents to block de novo protein synthesis or prevent protein degradation by ubiquitination, we found the stability of hypoxia inducible factor 1α (HIF-1α) protein was maintained in OSCC cells with HDAC2 overexpression. In addition, co-immunoprecipitation assay also revealed that HDAC2-mediated HIF-1α protein stability is because of direct interaction of HIF-1α with von Hippel-Lindau (VHL) protein. CONCLUSIONS: Our work demonstrates that HDAC2 maintains HIF-1α stability, probably at the level of protein modification, which in turn leads to the increase in cell invasion/migration ability in oral cancer progression. These findings implicate the potential of HDAC inhibitors for oral cancer therapy.


Assuntos
Carcinoma de Células Escamosas/patologia , Histona Desacetilase 2/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neoplasias Bucais/patologia , Animais , Carcinoma de Células Escamosas/secundário , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desacetilase 2/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metástase Linfática/patologia , Lisina/metabolismo , Camundongos , Camundongos SCID , Invasividade Neoplásica , Transplante de Neoplasias , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Distribuição Aleatória , Ubiquitinação/genética , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia
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