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MicroRNA-10b promotes pancreatic cancer cell invasion by suppressing TIP30 and enhancing EGF and TGF-[beta] actions / by Haoxu Ouyang

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Author	Ouyang, Haoxu.
Title	MicroRNA-10b promotes pancreatic cancer cell invasion by suppressing TIP30 and enhancing EGF and TGF-[beta] actions / by Haoxu Ouyang
Date	2013
Abstract	MicroRNA-10b (miR-10b) is considered a marker of disease aggressiveness in pancreatic ductal adenocarcinoma (PDAC), in view of the fact that lower levels of miR-10b are associated with better response to neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. To assess the underlying mechanisms, miR-10b precursor was overexpressed in pancreatic cancer cell lines, and microarray analysis, cell migration, cell invasion and signaling studies were conducted. Gene profiling identified several potential targets downregulated by miR-10b, including Tatinteractive protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b and siRNA-mediated silencing to TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b, whereas the actions of EGF in the presence of miR-10b were abrogated by EGF receptor (EGFR) kinase inhibition with erlotinib, and by the combined actions of the PI3K inhibitor LY294002 and the MEK inhibitor UO126. EGF-induced EGFR tyrosine phosphorylation, and ERK and AKT phosphorylation were enhanced by miR-10b, whereas phosphorylation of p38 MAPK was slightly attenuated. Moreover, the combination of miR-10b, EGF and transforming growth factor beta (TGF-[beta]) resulted in markedly increased cell migration and invasion in association with enhanced epithelial-mesenchymal transition (EMT). MiR-10b also decreased the expression of genes with potential anti-metastatic functions such as RAP2A, EPHB2, KLF4, SDC1 and NF1. Thus, miR-10b promotes pancreatic cancer cell invasion by suppressing TIP30 which enhances EGFR signaling through ERK/PI3K, and by facilitating EGF-TGF-[beta] cross-talk leading to EMT. Therefore, targeting miR-10b in PDAC may suppress matastasis by multiple complementary mechanisms and may also serve to interrupt deleterious EGF-TGF-[beta] interactions.
Description	x, 125 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Murray Korc, Ethan Dmitrovsky, James DiRenzo, Patricia Ernst
College	Dartmouth Medical School. Experimental and Molecular Medicine Program.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.995

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MicroRNA-10b promotes pancreatic cancer cell invasion by suppressing TIP30 and enhancing EGF and TGF-[beta] actions / by Haoxu Ouyang

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