title: MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells.
abstract: Pancreatic cancer (PC) has the worst prognosis among all cancers due to its late diagnosis and lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in PC and functionally involved in malignant phenotypes, is critical to achieve early diagnosis and development of effective therapeutic strategies. We have shown previously that MUC4, an aberrantly overexpressed transmembrane mucin, promotes growth, invasion and metastasis of PC cells, thus underscoring its potential as a clinical target. Here, we report a novel microRNA (miRNA)-mediated mechanism underlying aberrant expression of MUC4 in PC. We demonstrate that the 3' untranslated region of MUC4 contains a highly conserved miRNA-150 (miR-150) binding motif and its direct interaction with miR-150 downregulates endogenous MUC4 protein levels. We also show that miR-150-mediated MUC4 downregulation is associated with a concomitant decrease in human epidermal growth factor receptor 2 and its phosphorylated form, leading to reduced activation of downstream signaling. Furthermore, our findings demonstrate that miR-150 overexpression inhibits growth, clonogenicity, migration and invasion and enhances intercellular adhesion in PC cells. Finally, our data reveal a downregulated expression of miR-150 in malignant pancreatic tissues, which is inversely associated with MUC4 protein levels. Altogether, these findings establish miR-150 as a novel regulator of MUC4 and a tumor suppressor miRNA in PC.
authors: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604-1405, USA.
authors: Sanjeev K
authors: SK
authors: Srivastava
authors: Arun
authors: A
authors: Bhardwaj
authors: Seema
authors: S
authors: Singh
authors: Sumit
authors: S
authors: Arora
authors: Bin
authors: B
authors: Wang
authors: William E
authors: WE
authors: Grizzle
authors: Ajay P
authors: AP
authors: Singh
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055264:Mucin-4 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012323:RNA Processing, Post-Transcriptional; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D055264:Mucin-4; C533097:MIR150, human; C524658:MUC4 protein, human