Dataset Information

MicroRNA-23a promotes pancreatic cancer metastasis by targeting epithelial splicing regulator protein 1.

ABSTRACT: miR-23a plays vital roles in various cancer metastases. Here, we found that miR-23a expression was significantly up-regulated in pancreatic cancer tissues compared with adjacent normal tissues. miR-23a up-regulation was significantly associated with differentiated degree, lymphoid nodal status, tumor invasion and poor survival rate in pancreatic cancer patients. We also found that miR-23a expression was significantly up-regulated in lymph node metastatic tissues and in pancreatic cancer cells that underwent epithelial-mesenchymal transition (EMT). miR-23a down-regulation blocked TGF-β1-induced EMT and reversed the phenotype of EMT in Panc-1 cells. Furthermore, miR-23a down-regulation inhibited Panc-1 cells migration and invasion in vitro and liver metastases in vivo. But the effect of miR-23a up-regulation in Aspc-1 cells was opposite to that of miR-23a down-regulation in Panc-1 cells. Epithelial splicing regulatory protein 1 (ESRP1) was identified as a direct target of miR-23a. Restoration of ESRP1 rescued the effect of miR-23a on pancreatic cancer cell progression. Moreover, miR-23a up-regulation in Aspc-1 cells induced a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) together with increased FGFR2 IIIc mRNA levels, and decreased FGFR2 IIIb expression during EMT. But the effect of miR-23a down-regulation in Panc-1 cells was opposite to that of miR-23a up-regulation in Aspc-1 cells. In addition, the effect of miR-23a up-regulation was partly reversed by ESRP1 over-expression. Taken together, our findings indicated that miR-23a functions as an oncogene by regulating ESRP1 in pancreatic cancer.

SUBMITTER: Wu G

PROVIDER: S-EPMC5669934 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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

MicroRNA-23a promotes pancreatic cancer metastasis by targeting epithelial splicing regulator protein 1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets