RESUMEN
PROPOSE: We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC). METHODS: Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets. RESULTS: A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC. CONCLUSIONS: ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.
Asunto(s)
Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Perfilación de la Expresión Génica/métodos , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias del Colon/metabolismo , Supervivencia sin Enfermedad , Regulación hacia Abajo/genética , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Péptido Liberador de Gastrina/genética , Péptido Liberador de Gastrina/metabolismo , Regulación Neoplásica de la Expresión Génica , Marcadores Genéticos , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Estimación de Kaplan-Meier , Análisis por Micromatrices , Murinae , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Riesgo , Regulación hacia Arriba/genéticaRESUMEN
PROPOSE: We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC). METHODS: Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets. RESULTS: A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC. CONCLUSIONS: ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.
Asunto(s)
Humanos , Animales , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Perfilación de la Expresión Génica/métodos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Marcadores Genéticos , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Regulación hacia Arriba/genética , Factores de Riesgo , Neoplasias del Colon/metabolismo , Supervivencia sin Enfermedad , Péptido Liberador de Gastrina/genética , Péptido Liberador de Gastrina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Análisis por Micromatrices , Murinae , Estimación de Kaplan-Meier , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismoRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Péptido Liberador de Gastrina/administración & dosificación , Receptores de Bombesina/genética , Sinoviocitos/metabolismo , Animales , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromonas/administración & dosificación , Fibroblastos/efectos de los fármacos , Péptido Liberador de Gastrina/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Morfolinas/administración & dosificación , Fosfatidilinositol 3-Quinasas/genética , Fosforilación/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacos , Sinoviocitos/efectos de los fármacos , Sinoviocitos/patologíaRESUMEN
Nerve fibers and neurotransmitters have increasingly been shown to have a role in tumor progression. Gastrin-releasing peptide is a neuropeptide linked to tumor aggressiveness, acting as an autocrine tumor growth factor by binding to its receptor, gastrin-releasing peptide receptor, expressed by many tumors. Although neuropeptides have been previously linked to tumor cell proliferation, more recent studies have uncovered roles for neuropeptides in chemotaxis and metastasis. Understanding the precise roles of such peptides in cancer is crucial to optimizing targeted therapy design. We have previously described that gastrin-releasing peptide acts directly as a chemotactic factor for neutrophils, dependent on PI3K, ERK, and p38. In this study, we investigated roles for gastrin-releasing peptide in lung adenocarcinoma. We asked if gastrin-releasing peptide would act as a proliferative and/or chemotactic stimulus for gastrin-releasing peptide receptor-expressing tumor cells. In A549 cells, a non-small cell lung carcinoma line, the treatment with gastrin-releasing peptide leads to activation of AKT and ERK1/2, and production of reactive oxygen species. Gastrin-releasing peptide induced migration of A549 cells, dependent on gastrin-releasing peptide receptor and PI3K, but not ERK. However, no proliferation was observed in these cells in response to gastrin-releasing peptide, and gastrin-releasing peptide did not promote resistance to treatment with a chemotherapy drug. Our results suggest that, similar to what happens in neutrophils, gastrin-releasing peptide is a migratory, rather than a proliferative, stimulus, for non-small cell lung carcinoma cells, indicating a putative role for gastrin-releasing peptide and gastrin-releasing peptide receptor in metastasis.
Asunto(s)
Adenocarcinoma/genética , Carcinogénesis/genética , Péptido Liberador de Gastrina/genética , Neoplasias Pulmonares/genética , Receptores de Bombesina/genética , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Antineoplásicos/administración & dosificación , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Péptido Liberador de Gastrina/administración & dosificación , Péptido Liberador de Gastrina/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas/genética , Proteína Oncogénica v-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores de Bombesina/metabolismoRESUMEN
BACKGROUND: Pituitary tumors account for approximately 10-15% of intracranial neoplasms. AIM: Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1 (cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen- regulated, growth inhibitor). MATERIAL AND METHODS: The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR. RESULTS: A significantly higher content of CRABP1 mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary. CONCLUSIONS: The findings of differential expression of CRABP1 in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/metabolismo , Adenoma/metabolismo , GTP Fosfohidrolasas , Péptido Liberador de Gastrina , Neoplasias Hipofisarias/metabolismo , ARN Mensajero/metabolismo , Receptores de Ácido Retinoico , Adenoma Hipofisario Secretor de ACTH/genética , Adenoma/genética , Adolescente , Adulto , Anciano , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Péptido Liberador de Gastrina/genética , Péptido Liberador de Gastrina/metabolismo , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Hipófisis/metabolismo , Neoplasias Hipofisarias/genética , Prolactina/metabolismo , ARN Mensajero/genética , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Adulto JovenRESUMEN
Medulloblastoma is the most common brain tumor of childhood. Emerging molecular targets in medulloblastoma include neurotrophin and neuropeptide receptors. In the present study, we have examined the influence of brain-derived neurotrophic factor (BDNF)/TrkB receptor- and gastrin-releasing peptide receptor (GRPR)-mediated signaling on the viability of human medulloblastoma cells. The expression of TrkB and GRPR was confirmed by immunohistochemistry and mRNA for both BDNF and GRPR was detected by reverse transcriptase polymerase chain reaction in Daoy, D283, and ONS76 cells. Treatment with BDNF significantly inhibited the viability of Daoy and D283, but not ONS76 cells, measured with the MTT assay. Neither the GRPR agonists GRP and bombesin nor the GRPR antagonist RC-3095 affected cell viability. Because previous findings have indicated that the viability of glioma cells might be enhanced by GRP when combined with the cAMP phosphodiesterase-4 (PDE4) inhibitor rolipram, we also examined the effects of rolipram alone or combined with GRP on cell viability. Rolipram significantly reduced the viability of all three cell lines, and the inhibitory effect of rolipram in Daoy cells was not modified by cotreatment with GRP. The results suggest that BDNF/TrkB and PDE4, but not the GRPR, regulate the viability of medulloblastoma cells.