RESUMO
Heterozygous mutations in any of three major genes, BRCA1, BRCA2 and PALB2, are associated with high-risk hereditary breast cancer susceptibility frequently seen as familial disease clustering. PALB2 is a key interaction partner and regulator of several vital cellular activities of BRCA1 and BRCA2, and is thus required for DNA damage repair and alleviation of replicative and oxidative stress. Little is however known about how PALB2-deficiency affects cell function beyond that, especially in the three-dimensional setting, and also about its role during early steps of malignancy development. To answer these questions, we have generated biologically relevant MCF10A mammary epithelial cell lines with mutations that are comparable to certain clinically important PALB2 defects. We show in a non-cancerous background how both mono- and biallelically PALB2-mutated cells exhibit gross spontaneous DNA damage and mitotic aberrations. Furthermore, PALB2-deficiency disturbs three-dimensional spheroid morphology, increases the migrational capacity and invasiveness of the cells, and broadly alters their transcriptome profiles. TGFß signaling and KRT14 expression are enhanced in PALB2-mutated cells and their inhibition and knock down, respectively, lead to partial restoration of cell functions. KRT14-positive cells are also more abundant with DNA damage than KRT14-negative cells. The obtained results indicate comprehensive cellular changes upon PALB2 mutations, even in the presence of half dosage of wild type PALB2 and demonstrate how PALB2 mutations may predispose their carriers to malignancy.
Assuntos
Neoplasias , Transdução de Sinais , Humanos , Reparo do DNA , Células Epiteliais , Mama , Proteína do Grupo de Complementação N da Anemia de Fanconi/genéticaRESUMO
Triple-negative breast cancer (TNBC) is one of the most common malignancies worldwide and shows maximum invasiveness and a high risk of metastasis. Recently, many natural compounds have been highlighted as a valuable source of new and less toxic drugs to enhance breast cancer therapy. Among them, S-adenosyl-L-methionine (AdoMet) has emerged as a promising anti-cancer agent. MicroRNA (miRNA or miR)-based gene therapy provides an interesting antitumor approach to integrated cancer therapy. In this study, we evaluated AdoMet-induced modulation of miRNA-34c and miRNA-449a expression in MDA-MB-231 and MDA-MB-468 TNBC cells. We demonstrated that AdoMet upregulates miR-34c and miR-449a expression in both cell lines. We found that the combination of AdoMet with miR-34c or miR-449a mimic strongly potentiated the pro-apoptotic effect of the sulfonium compound by a caspase-dependent mechanism. For the first time, by video time-lapse microscopy, we showed that AdoMet inhibited the in vitro migration of MDA-MB-231 and MDA-MB-468 cells and that the combination with miR-34c or miR-449a mimic strengthened the effect of the sulfonium compound through the modulation of ß-catenin and Small Mother Against Decapentaplegic (SMAD) signaling pathways. Our results furnished the first evidence that AdoMet exerts its antitumor effects in TNBC cells through upregulating the expression of miR-34c and miR-449a.
Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MicroRNAs/genética , S-Adenosilmetionina/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima/efeitos dos fármacosRESUMO
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
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
Phosphorylation of Pyruvate Kinase M2 (PKM2) on Tyr105 by fibroblast growth factor receptor 1 (FGFR1) has been shown to promote its nuclear localization as well as cell growth in lung cancer. Better understanding the regulation of this process would benefit the clinical treatment for lung cancer. Here, it has been found that the adaptor protein receptor for activated PKC kinase (RACK1) formed a complex with FGFR1 and PKM2, and activated the FGFR1/PKM2 signaling. Knocking down the expression of RACK1 impaired the phosphorylation on Tyr105 of PKM2 and inhibited the growth and migration of lung cancer cells, while over-expression of RACK1 in lung cancer cells led to the resistance to Erdafitinib. Moreover, knocking down the expression of RACK1 impaired the tumorigenesis of lung cancer driven by LKB loss and mutated Ras (KrasG12D). Taken together, our study demonstrated the pivotal roles of RACK1 in FGFR1/PKM2 signaling, suggesting FGFR1/RACK1/PKM2 might be a therapeutic target for lung cancer treatment.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/patologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Superfície Celular/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/análise , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação ao GTP/análise , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/análise , Camundongos , Proteínas de Neoplasias/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptores de Quinase C Ativada , Receptores de Superfície Celular/análise , Hormônios Tireóideos/análise , Proteínas de Ligação a Hormônio da TireoideRESUMO
INTRODUCTION: Previous studies have reported that specific depletion of mammalian sterile-like kinase (MST1) in the mouse liver driven Hepatocellular carcinoma (HCC). However, how the expression of MST1 was regulated in the progression of HCC remains largely unknown. MATERIALS AND METHODS: The expression of miR-3910 in the HCC tissues and cell lines were examined using q-PCR. The functions of miR-3910 in HCC were examined using MTT assay, Boyden chamber assay and soft agar assay. The effects of miR-3910 on the metastasis of HCC cells were evaluated using the mouse model. RESULTS: Here, we have shown that miR-3910 regulated the expression of MST1. MiR-3910 was up-regulated in HCC samples and cell lines, and the expression of miR-3910 was induced by the oncogenic RasV12. In the functional study, miR-3910 was found to promote the growth and migration of HCC cells, and knocking down miR-3910 inhibited the metastasis of HCC cells. Mechanically, it was found that miR-3910 activated YAP signaling by targeting MST1. CONCLUSION: Taken together, this study demonstrated that miR-3910 exerted oncogenic effects on the progression of HCC and suggested that miR-3910 might be a therapeutic target for cancer therapy.
Assuntos
Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Biologia Computacional , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , MicroRNAs/genética , Invasividade Neoplásica , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição , Transfecção , Proteínas de Sinalização YAPRESUMO
Abnormalities in endosomes, or dysregulation in their trafficking, play an important role directly in many diseases including oncogenesis. Syntaxin-6 (STX6) is involved in diverse cellular functions in a variety of cell types and has been shown to regulate many intracellular membrane trafficking events such as endocytosis, recycling and anterograde and retrograde trafficking. However, its expression pattern and biological functions in esophageal squamous cell carcinoma (ESCC) remained unknown. Here, we have found that the expression of STX6 was up-regulated in ESCC samples, its expression was significantly correlated with tumor size, histological differentiation, lymph node metastasis and depth. On one hand, STX6 silencing inhibited ESCC cells viability and proliferation in a p53-dependent manner. On the other hand, STX6 effect integrin trafficking and regulate ESCC cells migration. Taken together, our study revealed the oncogenic roles of STX6 in the progression of ESCC, and it might be a valuable target for ESCC therapy.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Proteínas Qa-SNARE/metabolismo , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Integrina alfa3/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Qa-SNARE/antagonistas & inibidores , Proteínas Qa-SNARE/genética , RNA Interferente Pequeno/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para CimaRESUMO
MicroRNAs (miRNAs) play an important role in the tumorigenesis of ovarian cancer. Previously, we have reported the dysregulation of miR-203 in the ovarian cancer tissues. However, the biological functions and molecular mechanisms of miR-203 in ovarian cancer remain unknown. Here, we showed that the expression of miR-203 was increased in ovarian cancer tissues compared with the adjacent non-cancerous tissues and the transcription of miR-203 was inhibited by P53. Forced expression of miR-203 in ovarian cancer promoted cell growth and migration, while depletion of miR-203 inhibited the growth and migration of ovarian cancer cells. In addition, miR-203 promoted the metastasis of ovarian cancer cells in vivo and shorted the survival of the nude mice. Mechanically, miR-203 targeted the 3'-UTR of pyruvate dehydrogenase B (PDHB) and increased the consumption of glucose and the production of lactate. Overexpression of PDHB abolished the oncogenic effects of miR-203 on the growth of ovarian cancer cells. Together, our data suggested the oncogenic roles of miR-203 in ovarian cancer by promoting glycolysis, and miR-203 might be a therapeutic target for ovarian cancer.
Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Glicólise/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Complexo Piruvato Desidrogenase/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Glucose/metabolismo , Células HEK293 , Humanos , Ácido Láctico/biossíntese , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Metabolism alteration is one of the hallmarks of cancer cells. Although several studies have demonstrated that glycolysis played important roles in the progression of nasopharyngeal carcinoma (NPC), the functions of specific metabolism-associated genes remain largely unknown. In this study, it was found that Pyruvate dehydrogenase B (PDHB), which catalyzed the conversion of pyruvate to Acetyl-CoA, was downregulated in NPC cells. Forced expression of PDHB in NPC cells inhibited cell growth and migration, while knocking down the expression of PDHB promoted the growth, migration, and tumorigenesis of NPC cells. Mechanism study showed that PDHB inhibited ERK signaling and cell growth driven by RasV12. Collectively, our study demonstrated the suppressive roles of PDHB in the progression of NPC, and restoring the function of PDHB might be a promising strategy for NPC therapy.
Assuntos
Carcinoma/patologia , Neoplasias Nasofaríngeas/patologia , Proteínas de Neoplasias/fisiologia , Piruvato Desidrogenase (Lipoamida)/fisiologia , Animais , Carcinoma/enzimologia , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Silenciamento de Genes , Glicólise , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Neoplasias Nasofaríngeas/enzimologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Piruvato Desidrogenase (Lipoamida)/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de SinaisRESUMO
Dysregulation of Hippo-Yes-associate protein (YAP) signaling has important roles in the tumorigenesis of hepatocellular carcinoma (HCC). Our previous studies have shown that Cip1 interacting zinc finger protein 1 (CIZ1) activated YAP signaling in the HCC cells and promoted the growth and migration of cancer cells. However, the mechanisms for the activation of YAP signaling by CIZ1 are unknown. In this study, it was found that CIZ1 interacted with the transcriptional factor YAP in HCC cells. The nuclear matrix anchor domain of CIZ1 is responsible for its interaction with YAP. Moreover, CIZ1 enhanced the interaction between YAP and TEAD. Knocking down the expression of CIZ1 impaired the transcriptional activity as well as the biological functions of YAP. Taken together, our study demonstrated that CIZ1 is a positive regulator of YAP signaling, and CIZ1 might be a therapeutic target for HCC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Imunoprecipitação , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Nucleares/genética , Fosfoproteínas/genética , Fatores de Transcrição , Transcrição Gênica , Proteínas de Sinalização YAPRESUMO
Dysregulation of protein arginine methyltransferase 1 (PRMT1) has been reported in several cancer types. However, its expression pattern and biological functions in esophageal squamous cell carcinoma (ESCC) remained unknown. Here, we have found that the expression of PRMT1 was up-regulated in ESCC samples. In the biological function studies, forced expression of PRMT1 promoted the growth and migration of ESCC cells. However, knocking down the expression of PRMT1 inhibited the growth, migration, and metastasis of ESCC cells. Moreover, PRMT1 activated Hedgehog signaling and up-regulated the expression of target genes downstream of Hedgehog signaling. Taken together, our study revealed the oncogenic roles of PRMT1 in the progression of ESCC, and PRMT1 might be a promising therapeutic target for the treatment of ESCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteínas Repressoras/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica/genética , Proteínas Hedgehog/genética , Humanos , Transdução de Sinais/genética , Regulação para Cima/genéticaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies in the world. Numerous studies have linked the activation of AKT to the progression of PDAC. Phosphatidylethanolamine-binding protein 4 (PEBP4) has been reported to be upregulated in various cancer types. However, its expression pattern and biological functions in PDAC are unknown. In this study, it was found that the messenger RNA (mRNA) and protein level of PEBP4 was elevated in PDAC samples. Forced expression of PEBP4 in PDAC cell lines promoted cell growth and migration, while downregulation of PEBP4 in PDAC cells by RNA interference (RNAi) inhibited the growth, migration, and metastasis of the cancer cells. PEBP4 interacted with AKT and promoted the phosphorylation of serine 473 in AKT. Collectively, this study suggested that PEBP4 might promote the progression of PDAC through activating AKT signaling and PEBP4 might be a promising therapeutic target for PDAC treatment.
Assuntos
Carcinoma Ductal Pancreático/patologia , Movimento Celular , Neoplasias Pancreáticas/patologia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Animais , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/fisiologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Neoplasias Pancreáticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
RND1 is reported to control the dynamics of cytoskeleton, cell growth, and survival, and dysregulation of RND1 is involved in the tumorigenesis. However, its expression and functions in the esophageal squamous cell carcinoma (ESCC) are unknown. In the present study, it was found that the expression of RND1 was up-regulated in ESCC tissues compared with the adjacent normal tissues. Forced expression of RND1 promoted the growth and migration of ESCC cells, while knocking down the expression of RND1 inhibited the growth, migration, and metastasis of ESCC cells. Molecular mechanism studies showed that RND1 activated ERK signaling. In summary, our study suggested that RND1 plays an important role in the progression of ESCC, and RND1 might be a promising target for the treatment of ESCC.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citoesqueleto/metabolismo , Progressão da Doença , Carcinoma de Células Escamosas do Esôfago , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Fosforilação , Transdução de SinaisRESUMO
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
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
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
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
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.