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Imbalanced expression of Tif1? inhibits pancreatic ductal epithelial cell growth.

ABSTRACT: Transcriptional intermediary factor 1 gamma (Tif1?) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGF? pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1? interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1? inhibits transcriptional activity of the Smad1/Smad4 complex through its PHD domain or bromo-domainin pancreatic cells by luciferase assay. Additionally, there is a dynamic inverse relationship between the levels of Tif1? and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1? resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1? resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1? reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1? results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1? may inhibit tumor invasion. These data suggest that Tif1? might serve as a potential therapeutic target for pancreatic cancer.

SUBMITTER: Ligr M

PROVIDER: S-EPMC4065401 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Imbalanced expression of Tif1γ inhibits pancreatic ductal epithelial cell growth.

Ligr Martin M Wu Xinyu X Daniels Garrett G Zhang David D Wang Huamin H Hajdu Cristina C Wang Jinhua J Pan Ruimin R Pei Zhiheng Z Zhang Lanjing L Melis Marcovalerio M Pincus Matthew R MR Saunders John K JK Lee Peng P Xu Ruliang R

American journal of cancer research 20140526 3

Transcriptional intermediary factor 1 gamma (Tif1γ) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGFβ pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1γ interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. ...[more]

PMID: 24959375

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Project description:BackgroundCell competition is an important feature in pancreatic cancer (PC) progression, but the underlying mechanism remains elusive. This study aims to explore the role of exosomes derived from normal pancreatic ductal epithelial cells involved in PC progression.MethodsPC cells and pancreatic stellate cells (PSCs) were treated with exosomes isolated from pancreatic ductal epithelial cells. Cell proliferation was assessed by CCK8 assays. Cell migration and invasion were assessed by Transwell assays. PC and matched adjacent non-tumor tissue specimens were obtained from 46 patients pathologically diagnosed with PC at Peking University First Hospital from 2013 to 2017. Tissue miR-485-3p and p21-activated kinase-1 (PAK1) expression was examined by real-time polymerase chain reaction (RT-PCR), and the relationship of the two was analyzed using Pearman's product-moment correlation. The clinical significance of miR-485-3p was analyzed using the Chi-square test, Wilcoxon rank-sum test, and Fisher exact probability, respectively. The binding of miR-485-3p to PAK1 5'-untranslated region (5'-UTR) was examined by luciferase assay. PC cells were xenografted into nude mice as a PC metastasis model.ResultsExosomes from pancreatic ductal epithelial cells suppressed PC cell migration and invasion as well as the secretion and migration of PSCs. MiR-485-3p was enriched in the exosomes of pancreatic ductal epithelial cells but deficient in those of PC cells and PSCs, in accordance with the lower level in PSCs and PC cells than that in pancreatic ductal cells. And the mature miR-485-3p could be delivered into these cells by the exosomes secreted by normal pancreatic duct cells, to inhibit PC cell migration and invasion. Clinical data analysis showed that miR-485-3p was significantly decreased in PC tissues (P < 0.05) and was negatively associated with lymphovascular invasion (P = 0.044). As a direct target of miR-485-3p, PAK1 was found to exert an inhibitory effect on PC cells, and there was a significantly negative correlation between the expression levels of miR-485-3p and PAK1 (r = -0.6525, P < 0.0001) in PC tissues. Moreover, miR-485-3p could suppress PC metastasis in vivo by targeting p21-activated kinase-1.ConclusionsExosomal miR-485-3p delivered by normal pancreatic ductal epithelial cells into PC cells inhibits PC metastasis by directly targeting PAK1. The restoration of miR-485-3p by exosomes or some other vehicle might be a novel approach for PC treatment.

Dataset Information

Imbalanced expression of Tif1? inhibits pancreatic ductal epithelial cell growth.

Publications

Imbalanced expression of Tif1γ inhibits pancreatic ductal epithelial cell growth.

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