miR-145-dependent targeting of Junctional Adhesion Molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness.
Götte M, Mohr C, Koo CY, Stock C, Vaske AK, Viola M, Ibrahim SA, Peddibhotla S, Teng YH, Low JY, Ebnet K, Kiesel L, Yip GW
Research article (journal) | Peer reviewedAbstract
Micro RNAs are small non-coding RNAs, which regulate fundamental cellular and developmental processes at the transcriptional and translational level. In breast cancer, miR-145 expression is downregulated compared with healthy control tissue. As several predicted targets of miR-145 potentially regulate cell motility, we aimed at investigating a potential role for miR-145 in breast cancer cell motility and invasiveness. Assisted by Affymetrix array technology, we demonstrate that overexpression of miR-145 in MDA-MB-231, MCF-7, MDA-MB-468 and SK-BR-3 breast cancer cells and in Ishikawa endometrial carcinoma cells leads to a downregulation of the cell-cell adhesion protein JAM-A and of the actin bundling protein fascin. Moreover, podocalyxin and Serpin E1 mRNA levels were downregulated, and gamma-actin, transgelin and MYL9 were upregulated upon miR-145 overexpression. These miR-145-dependent expression changes drastically decreased cancer cell motility, as revealed by time-lapse video microscopy, scratch wound closure assays and matrigel invasion assays. Immunofluorescence microscopy demonstrated restructuring of the actin cytoskeleton and a change in cell morphology by miR-145 overexpression, resulting in a more cortical actin distribution, and reduced actin stress fiber and filopodia formation. Nuclear rotation was observed in 10% of the pre-miR-145 transfected MDA-MB-231 cells, accompanied by a reduction of perinuclear actin. Luciferase activation assays confirmed direct miR-145-dependent regulation of the 3'UTR of JAM-A, whereas siRNA-mediated knockdown of JAM-A expression resulted in decreased motility and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. Our data identify JAM-A and fascin as novel targets of miR-145, firmly establishing a role for miR-145 in modulating breast cancer cell motility. Our data provide a rationale for future miR-145-targeted approaches of antimetastatic cancer therapy.
Details about the publication
Authors from the University of Münster
| Ebnet, Klaus | Institute of Medical Biochemistry |
| Götte, Martin | Department of Gynecology and Obstetrics |
| Kiesel, Ludwig | Department of Gynecology and Obstetrics |
| Peddibhotla, Sree Durga Swetha | Sonderforschungsbereich 858 - "Synergetische Effekte in der Chemie - Von der Additivität zur Kooperativität" |
Promotionen, aus denen die Publikation resultiert
| Einfluss der mikroRNA miR-145 auf die Expression von Pathogenesefaktoren des Endometrium- und Mammakarzinoms Candidate: Vaske, Ann-Kathrin | Supervisors: Götte, Martin Period of time: 30/12/2007 - 30/10/2011 Doctoral examination procedure finished at: Doctoral examination procedure at University of Münster | |
| Functional analysis of Syndecan-1, a novel target of miR-10b, in breast cancer progression Candidate: Abdel-Aziz Ibrahim, Sherif | Supervisors: Götte, Martin; Liebau, Eva; Greve, Burkhard Period of time: 05/01/2008 - 19/07/2011 Doctoral examination procedure finished at: Doctoral examination procedure at University of Münster |