RESUMO
One of the major signaling pathways that determine the tumor aggression and patient outcome in pancreatic cancer is the transforming growth factor-beta (TGF-ß) pathway. It is inactivated at various levels in pancreatic cancer and plays a dual role in tumor initiation and progression. The Smad family of proteins transduce signals from the TGF-ß superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. This review discusses the structure, function and regulation of various participating Smad family members, and their individual roles in determining the progression and outcome of pancreatic cancer patients, with a special emphasis on Smad4.
Assuntos
Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteína Smad4/química , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad6/genética , Proteína Smad6/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Background: Smad4, Smad6 and Smad7 are important molecules in TGF-beta pathway, which plays an important role in pancreatic ductal adenocarcinoma (PDAC) biology. Aims : This study examined the expression profiles of Smad4, Smad6 and Smad7 mRNA in patient samples of PDAC and their relationship to Smad protein expression, SMAD4 gene mutations, clinicopathological parameters and patient survival. Settings and Design: Surgically resected, paired normal and tumor tissues of 25 patients of PDAC were studied. Materials and Methods: Protein and mRNA levels were assessed by immunohistochemistry and RT-PCR, respectively. Statistical Methods: Statistical analysis was done using Student's t-test, Pearson's chi-square test, Spearman's Rank Correlation, Pearson's Correlation test and Kaplan-Meier Logrank test. Results: While there was a highly significant difference in the protein levels of all three Smads in tumor as compared to normal samples, mRNA levels were significantly different only for Smad4. Protein levels did not correlate significantly with mRNA levels for any of the three Smads. The mRNA levels of Smad4 and Smad6, Smad4 and Smad7, and Smad6 and Smad7 in tumor samples showed a significant positive correlation. The relationship of Smad4 mRNA expression to SMAD4 gene status and Smad4 protein expression was discordant and there was no significant correlation between mRNA expression and clinicopathological parameters and patient survival. Conclusion : The absence of concordance between SMAD4 gene status, mRNA expression and Smad4 protein expression suggests the presence of other regulatory mechanisms in Smad4 transcription and translation in PDAC.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/secundário , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad6/genética , Proteína Smad6/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Taxa de SobrevidaRESUMO
The inhibitory Smad6 and Smad7 are responsible for cross-talk between TGF-beta/bone morphogenic protein (BMP) signaling and other cellular signaling pathways, as well as negative feedback on their own signaling functions. Although inhibitory Smads are induced by various stimuli, little is known about the stimuli that increase Smad6 transcription, in contrast to Smad7. Here we demonstrate that etoposide, which induces double strand breaks during DNA replication, significantly up-regulates the transcription of the Smad6 gene in CMT-93 mouse intestinal cells by increasing specific DNA binding proteins. In addition, endogenous inhibition of the Smad6 gene by RNAi interference led to transient accumulation of G1 phase cells and reduction in incorporation of bromodeoxyuridine (BrdU). These findings strongly suggest that Smad6 plays a distinct role in the signaling of etoposide-induced DNA damage.