RESUMO
Over-activation of beta-catenin/TCF signaling is very common in the progression of hepatocellular carcinoma (HCC). The molecular mechanisms leading to the aberrant activation of beta-catenin/TCF signaling are not fully understood. In this study, it was found that CDK7 was up-regulated in HCC tissues and its expression inversely correlated with the survival of HCC patients. Functional study showed that CDK7 promoted the growth and migration of HCC cells, and knocking down the expression of CDK7 inhibited the growth of HCC cells in both liquid culture and soft agar. Mechanistically, CDK7 interacted with beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of CDK7 in HCC and suggested that CDK7 might be a promising therapeutic target.
Assuntos
Carcinoma Hepatocelular/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Transdução de Sinais/fisiologia , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismo , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Several studies have indicated the involvement of DLX1 in the progression of prostate cancer. However, the functions of DLX1 in the prostate cancer and the underlying molecular mechanism remains largely unknown. In this study, we have shown that DLX1 was up-regulated in the prostate clinical samples. DLX1 promoted the growth, migration and colony formation of prostate cancer cells by activating beta-catenin/TCF signaling. DLX1 interacted with beta-catenin and enhanced the interaction between beta-catenin and TCF4. Taken together, this study demonstrated that DLX1 exerted the oncogenic roles on the prostate cancer by activating beta-catenin/TCF signaling.
Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas de Homeodomínio/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Próstata/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Wnt ligand binding initiates the interaction between Frizzled and Dvl proteins. However, the regulation of Frizzled-Dvl proteins interaction remains largely unknown. AIMS: The present study aims to elucidate the regulation of Frizzled-Dvl interaction by WDR34. METHODS: The protein levels of WDR34 in hepatocellular carcinoma (HCC) tissues were examined by western blot and immunohistochemistry. The effects of WDR34 on the growth and migration of HCC cells were examined using MTT assay and Boyden chamber assay. The interaction between Frizzled and Dvl was evaluated by immunoprecipitation and GST pull-down assay. RESULTS: In this study, we have shown that WDR34, the binding protein of Frizzled (Fz) activated beta-catenin/TCF signaling by enhancing the interaction between Fz and Dvl2. WDR34 was found to up-regulate in HCC tissues, and its expression was negatively correlated with the survival of HCC patients. WDR34 promoted the growth, colony formation and migration of HCC cells. However, knocking down the expression of WDR34 inhibited the growth, colony formation and migration of HCC cells. CONCLUSION: Taken together, this study demonstrated the oncogenic roles of WDR34 in the progression of HCC and suggested that WDR34 might be a therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas Desgrenhadas/metabolismo , Receptores Frizzled/metabolismo , Neoplasias Hepáticas/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas , Taxa de Sobrevida , Regulação para CimaRESUMO
The enhanced ability of cancer cell migration and metastasis is the major cause for the cancer-related death of hepatocellular carcinoma (HCC). Better understanding the mechanisms for the motility of cancer cells will benefit the treatment. Diaphanous-related formin 3 (DIAPH3) has been reported to regulate the motility of cells by remodeling the cytoskeleton. However, the mechanism through which DIAPH3 regulated the motility of cancer cells remains largely unknown. In this study, we have shown that the expression of DIAPH3 was up-regulated in HCC. DIAPH3 positively regulated the growth, migration, colony formation, epithelia mesenchymal transition, and metastasis of HCC cells. Mechanically, DIAPH3 activated the beta-catenin/TCF signaling by binding HSP90 and disrupting the interaction between GSK3beta and HSP90. Taken together, our study demonstrated the oncogenic activity of DIAPH3 in the progression of HCC and suggested that PDIAPH3 might be a therapeutic target.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/patologia , Forminas , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Metástase NeoplásicaRESUMO
Over-activation of beta-catenin/TCF signaling has been frequently observed in hepatocellular carcinoma (HCC). Better understanding the molecular mechanism for the aberrant activation of beta-catenin/TCF signaling would provide novel insights into the treatment of this malignancy. In this study, we have shown that the expression of PKMYT1 was up-regulated in HCC. PKMYT1 positively regulated the growth, migration, colony formation, metastasis and epithelia mesenchymal transition (EMT) of HCC cells. Mechanically, PKMTY1 activated the beta-catenin/TCF signaling by binding and inactivating GSK3beta. Taken together, our study demonstrated the oncogenic activity of PKMYT1 in the progression of HCC and suggested that PKMYT1 might be a therapeutic target.
Assuntos
Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismoRESUMO
Aberrant activation of beta-catenin/TCF signaling is one of the hallmarks of colon cancer. It is of great interest to study the mechanism for the regulation of beta-catenin/TCF signaling. In this study, it was found that LRP1B was down-regulated in colon cancer tissues and inhibited the growth, migration and metastasis of colon cancer cells. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. Taken together, our study demonstrated the suppressive roles of LRP1B in the progression of colon cancer, implicating that restoring the function of LRP1B would be a promising strategy for the treatment of colon cancer.
Assuntos
Movimento Celular/fisiologia , Proliferação de Células/genética , Neoplasias do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Receptores de LDL/metabolismo , Linhagem Celular Tumoral , Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo , Humanos , Transdução de Sinais/fisiologia , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismoRESUMO
Deregulated activation of ß-catenin in cancer has been correlated with genomic instability. During thymocyte development, ß-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of ß-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human T-ALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated ß-catenin promoted an antiapoptosis gene expression profile. Thus, activated ß-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.
Assuntos
Instabilidade Genômica , Ativação Linfocitária , Linfoma/genética , Linfócitos T/citologia , beta Catenina/metabolismo , Animais , Apoptose , Sequência de Bases , Sobrevivência Celular , Quebras de DNA de Cadeia Dupla , Metilação de DNA , Reparo do DNA , Modelos Animais de Doenças , Genes RAG-1/genética , Fator 1-alfa Nuclear de Hepatócito , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Recombinação Genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Timócitos/citologia , Translocação Genética , beta Catenina/genéticaRESUMO
Bone morphogenetic protein 10 (BMP10), a novel member of BMP family, has been identified as an important regulator for angiogenesis. Dysregulation of BMP has been observed in several cancer types. However, its roles in gastric cancer (GC) remain unknown. In this study, the expression of BMP10 was found to be down-regulated in GC samples. Forced expression of BMP10 in GC cells inhibited its growth and migration, while knocking down the expression of BMP10 in GC cells promoted cell growth, migration, and metastasis. BMP10 was shown to negatively regulated beta-catenin/TCF signaling by up-regulating Axin protein level. Taken together, the present study revealed the suppressive function of BMP10 in gastric cancer.
Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Movimento Celular , Proliferação de Células , Neoplasias Gástricas/patologia , Proteínas Morfogenéticas Ósseas/análise , Linhagem Celular Tumoral , Humanos , Metástase Neoplásica , Transdução de Sinais/fisiologia , Fatores de Transcrição TCF/fisiologia , beta Catenina/fisiologiaRESUMO
Increasing evidence indicated that tripartite motif containing 37 (TRIM37) was involved in the tumorigenesis of several cancer types. However, its expression pattern and biological functions in pancreatic ductal adenocarcinoma (PDAC) remained unknown. In this study, real-time PCR, Western blot and immunohistochemistry was performed to examine the expression of TRIM37 in the pancreatic cancerous tissues. Colony formation assay and cell migration assay were performed to study the functions of TRIM37 in pancreatic cancer cells. Dual-luciferase assay was performed to study the regulation of TRIM37 on beta-catenin/TCF signaling. It was found that the expression level of TRIM37 was significantly higher in pancreatic cancerous tissues compared with the adjacent normal tissues. Function analysis indicated that overexpression of TRIM37 promoted the growth and migration of the pancreatic cancer cells, while knocking down the expression of TRIM37 inhibited the growth and migration of the pancreatic cancer cells. The molecular mechanism study suggested that TRIM37 interacted with beta-catenin and activated the transcriptional activity of beta-catenin/TCF complex as well as the expression of its downstream target genes. Taken together, our study showed the oncogenic roles of TRIM37 in pancreatic cancer, and TRIM37 might be a promising target for pancreatic cancer treatment.
Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pâncreas/patologia , Transdução de Sinais/genética , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , beta Catenina/genética , Neoplasias PancreáticasRESUMO
Members of the Kruppel-like factor (KLF) family have been considered as the tumor suppressors for their inhibitory effects on cell proliferation. Dysregulation of KLF2, a member of KLF family, has been observed in various cancer types. However, its expression pattern and functions in the pancreatic ductal adenocarcinoma (PDAC) are unknown. In this study, we examined the expression of KLF2 in PDAC clinical samples and evaluated the functions of KLF2 in the progression of PDAC. KLF2 is shown to be downregulated in PDAC clinical samples and overexpression of KLF2 inhibits the growth, migration, and metastasis of PDAC cancer cells. KLF2 interacts with beta-catenin and negatively regulates the beta-catenin/TCF signaling. Taken together, this study suggests the suppressive functions of KLF2 in PDAC.
Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Fatores de Transcrição Kruppel-Like/fisiologia , Neoplasias Pancreáticas/patologia , Movimento Celular , Proliferação de Células , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/análise , Metástase Neoplásica , Transdução de Sinais/fisiologia , Fatores de Transcrição TCF/fisiologia , beta Catenina/fisiologiaRESUMO
Dys-regulation of serine-arginine protein kinase 1 (SRPK1) has been reported in non-small cell lung cancer (NSCLC). However, its functions in the progression of NSCLC remain poorly understood. In this study, the expression of SRPK1 in NSCLC tissues was determined using real-time PCR, and the roles of SRPK1 in the progression of NSCLC were investigated. It was found that both the mRNA level and the protein level of SRPK1 were up-regulated in NSCLC tissues. Forced expression of SRPK1 promoted the growth and migration of NSCLC cells, while knocking down the expression of SRPK1 inhibited the growth, migration, and tumorigenicity of NSCLC cells. Mechanism studies showed that SRPK1 activated the transcriptional activity of beta-catenin/T-cell factor (TCF) complex, and knocking down the expression of SRPK1 attenuated the expression of target genes of beta-catenin/T-cell factor (TCF) complex. In addition, silencing the expression of SRPK1 down-regulated the phosphorylation of GSK3beta. Taken together, SRPK1 might play an oncogenic role in NSCLC, and SRPK1 might be a therapeutic target for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Indução Enzimática , Células Epiteliais , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos Nus , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Fatores de Transcrição TCF/fisiologia , Ensaio Tumoral de Célula-Tronco , Regulação para Cima , beta Catenina/fisiologiaRESUMO
The transcriptional factor Forkhead box protein C2 (FOXC2) was recently demonstrated to be up-regulated in various cancer types. However, its expression profile and the biological functions in pancreatic cancer remain unknown. In this study, we examined the expression pattern of FOXC2 in pancreatic ductal adenocarcinoma (PDAC) tissues and investigated the functions of FOXC2 in the progression of PDAC. It was found that the expression of FOXC2 was up-regulated in PDAC samples. Forced expression of FOXC2 promoted the growth and migration of the PDAC cells, while knocking down the expression of FOXC2 inhibited the growth and migration of the PDAC cells. Moreover, FOXC2 was found to interact with beta-catenin and promote cell growth by activating beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of FOXC2 in PDAC, and FOXC2 might be a therapeutic target for PDAC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Pancreáticas/patologia , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Estudos de Casos e Controles , Seguimentos , Fatores de Transcrição Forkhead/genética , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Hepatocyte cell adhesion molecule (HEPACAM), a member of immunoglobulin superfamily, is an adhesion molecule. Although dysregulation of several adhesion molecules has been implicated in the progression of non-small cell lung cancer (NSCLC), the expression profile and functions of HEPACAM in NSCLC remains unknown. In this study, it was found that the expression of HEPACAM was downregulated in NSCLC tissues. Forced expression of HEPACAM in NSCLC cells inhibited the growth and migration of the cancer cells, while knocking down the expression of HEPACAM promoted cell growth, migration, and metastasis. In the molecular mechanism study, HEPACAM was found to be a negative regulator of beta-catenin/TCF signaling. Taken together, this study revealed the suppressive roles of HEPACAM in NSCLC and restoring the function of HEPACAM in NSCLC might be a promising strategy for the therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas/genética , Moléculas de Adesão Celular/genética , Proteínas de Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Transdução de Sinais/genética , beta Catenina/genéticaRESUMO
Transforming growth factor beta-inducing factor 1 (TGIF1) was reported to be dysregulated in several types of cancer. However, its expression pattern and functions in nonsmall cell lung cancer (NSCLC) remained unknown. In the present study, the expression of TGIF1 was found to be elevated in the clinical NSCLC tissues. TGIF1 promoted the growth and migration of NSCLC cells, while knocking down the expression of TGIF1 inhibited the growth and migration of NSCLC cells. Moreover, downregulation of TGIF1 impaired the metastasis of NSCLC cells. In the study for the molecular mechanisms, it was found that TGIF1 positively regulated beta-catenin/TCF signaling. In summary, our study demonstrated the oncogenic role of TGIF1 in NSCLC, and TGIF1 might be a therapeutic target for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Proteínas de Homeodomínio/biossíntese , Proteínas Repressoras/biossíntese , beta Catenina/genética , Animais , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Proteínas Repressoras/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF-1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF-1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over-expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta-catenin and inhibited beta-catenin/T-cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta-catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer.
Assuntos
Transformação Celular Neoplásica/patologia , Mucosa Gástrica/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Neoplasias Gástricas/prevenção & controle , Animais , Apoptose , Western Blotting , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Técnicas Imunoenzimáticas , Imunoprecipitação , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , RNA Interferente Pequeno/genética , Estômago/patologia , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
Overactivation of beta-catenin/TCF signaling in prostate cancer is very common. However, how the beta-catenin/TCF complex is regulated in the nucleus remains largely unknown. In this study, we have shown that NOL8, a binding protein of beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. NOL8 is up-regulated in the prostate cancer, and promoted the growth, migration and colony formation of cancer cells. Knocking down the expression of NOL8 inhibited the growth, migration and colony formation of prostate cancer cells. The molecular mechanism study demonstrated that NOL8 promoted the migration and colony formation of cancer cells by activating beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of NOL8 in prostate cancer and suggested that NOL8 might be an important therapeutic target for prostate cancer.
Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/patologia , beta Catenina/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Movimento Celular , Humanos , Masculino , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Fatores de Transcrição TCF/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genéticaRESUMO
Aberrant activation of beta-catenin/TCF (T-cell factor) signaling is frequently observed in the pancreatic cancer. However, the regulation of nuclear beta-catenin/TCF transcription machinery remains largely unknown. In this study, TFCP2 (transcriptional factor CP2) expression in pancreatic cancer was detected by qPCR, immunohistochemistry and western blot. Western blot, colony formation assay, migration and invasion experiment were performed to investigate the effects of TFCP2 on the growth and migration of pancreatic cancer cells. In vivo, mouse metastasis models were utilized to determine metastasis ability. Western blots were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of TFCP2 on beta-catenin/TCF signaling. We have shown that the transcription factor TFCP2 was up-regulated in the pancreatic cancer. Over-expression of TFCP2 promoted the growth, migration, invasion and colony formation of pancreatic cancer cells, while knocking down the expression of TFCP2 inhibited the growth, migration, invasion, colony formation and metastasis of pancreatic cancer cells. The mechanism study revealed that TFCP2 interacted beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. Taken together, our study demonstrated the oncogenic roles of TFCP2 in pancreatic cancer, and suggested that TFCP2 might be a target for the treatment of pancreatic cancer.
RESUMO
RAP1B is a small GTPase, which regulates multiple cellular processes. Up-regulation of RAP1B has been observed in several cancer types. Although previous study has shown that miR-518 inhibited the proliferation and invasion of esophageal squamous cell carcinoma (ESCC) cells possibly by targeting RAP1B, the expression pattern and the functions of RAP1B in ESCC are not fully understood. Here, we have fund that the expression of RAP1B was up-regulated in ESCC clinical samples. Gain-of-function and loss-of-function assays demonstrated that RAP1B promoted the growth, migration and metastasis of the ESCC cells. Moreover, the mechanism study showed that RAP1B interacted with DVL2, an important upstream regulator for beta-catenin/TCF signaling, and activated beta-catenin/TCF signaling. Taken together, our study demonstrated the oncogenic roles of RAP1B in ESCC, and suggested that RAP1B might be a therapeutic target.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas Desgrenhadas/metabolismo , Neoplasias Esofágicas/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas rap de Ligação ao GTP/metabolismo , Animais , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas Desgrenhadas/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos Nus , Metástase Neoplásica , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , beta Catenina/genética , Proteínas rap de Ligação ao GTP/genéticaRESUMO
Beta-catenin/TCF signaling has been reported to promote the growth and metastasis of pancreatic cancer cells. However, the regulation for the beta-catenin/TCF transcriptional complex remains largely unknown. Here, we have found that YEATS4 is a positive regulator for Beta-catenin/TCF signaling. The expression of YEATS4 was elevated in clinical pancreatic cancer samples and pancreatic cancer mouse model. Up-regulation of YEATS4 promoted the growth, migration and invasion of pancreatic cancer cells, while knocking down the expression of YEATS4 inhibited the growth, migration, invasion and metastasis of pancreatic cancer cells. Moreover, the mechanism study revealed that YEATS4 interacted with beta-catenin and activated beta-catenin/TCF signaling. Furthermore, knocking down the expression of YEATS4 impaired the malignant transformation of normal pancreatic cells (HPDE6C7) by the oncogenic Ras. Taken together, our study demonstrated the oncogenic roles of YEATS4 in the progression of pancreatic cancer by activating beta-catenin/TCF signaling and suggested that YEATS4 might be a promising therapeutic target for pancreatic cancer.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Fatores de Transcrição TCF/metabolismo , Fatores de Transcrição/genética , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia , Ensaio Tumoral de Célula-TroncoRESUMO
Aberrant activation of beta-catenin/TCF is a hallmark of colon cancer. How the functions of nuclear localized beta-catenin are regulated is not fully understood. Here, it was found that FOXN3 (Forkhead box N3) was down-regulated in colon cancer tissues. Forced expression of FOXN3 inhibited the growth, migration and invasion of colon cancer cells, while knocking down the expression of FOXN3 promoted the growth, migration, invasion and metastasis of colon cancer cells. FOXN3 bind to beta-catenin and inhibited beta-catenin/TCF signaling by blocking the interaction between beta-catenin and TCF4. Taken together, these data demonstrated the suppressive roles of FOXN3 in the progression of colon cancer, and indicated that restoring the functions of FOXN3 would be a novel therapeutic strategy for colon cancer.