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Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-? signaling pathway.

ABSTRACT: BACKGROUND:Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC). METHODS:Firstly, the function of TAM recruitment in PDAC tissues was assessed, followed by identification of the effects of M2 macrophage-derived exosomes on PDAC cell activities and tumor formation and metastasis in mice. In silico analysis was conducted to predict differentially expressed genes and regulatory miRNAs related to PDAC treated with macrophages, which determined miR-501-3p and TGFBR3 for subsequent experiments. Next, gain- and loss-of-function experiments were performed to examine their role in PDAC progression with the involvement of the TGF-? signaling pathway. RESULTS:TAM recruitment in PDAC tissues was associated with metastasis. Highly expressed miR-501-3p was observed in PDAC tissues and TAM-derived exosomes. Both M2 macrophage-derived exosomes and miR-501-3p promoted PDAC cell migration and invasion, as well as tumor formation and metastasis in nude mice. MiR-501-3p was verified to target TGFBR3. PDAC cells presented with down-regulated TGFBR3, which was further decreased in response to M2 macrophage treatment. TGF-? signaling pathway activation was implicated in the promotion of miR-501-3p in PDAC development. The suppression of macrophage-derived exosomal miR-501-3p resulted in the inhibition of tumor formation and metastasis in vivo. CONCLUSION:M2 macrophage-derived exosomal miR-501-3p inhibits tumor suppressor TGFBR3 gene and facilitates the development of PDAC by activating the TGF-? signaling pathway, which provides novel targets for the molecular treatment of PDAC.

SUBMITTER: Yin Z

PROVIDER: S-EPMC6631643 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-β signaling pathway.

Yin Zi Z Ma Tingting T Huang Bowen B Lin Lehang L Zhou Yu Y Yan Jinhai J Zou Yiping Y Chen Sheng S

Journal of experimental & clinical cancer research : CR 20190715 1

<h4>Background</h4>Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC).<h4>Methods</h4>Firstly, the function of TAM recruitment in PDAC tissues was assessed, followed by ...[more]

PMID: 31307515

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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.

Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion.MethodsIn-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers.ResultsmiR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing ?-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21.ConclusionsmiR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.

Dataset Information

Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-? signaling pathway.

Publications

Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-β signaling pathway.

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