Oncotarget

Research Papers:

A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice

Nicholas H. Farina, Areg Zingiryan, Jacqueline A. Akech, Cody J. Callahan, Huimin Lu, Janet L. Stein, Lucia R. Languino, Gary S. Stein and Jane B. Lian _

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Oncotarget. 2016; 7:70462-70474. https://doi.org/10.18632/oncotarget.11992

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Abstract

Nicholas H. Farina1, Areg Zingiryan1, Jacqueline A. Akech2, Cody J. Callahan1, Huimin Lu3, Janet L. Stein1, Lucia R. Languino3, Gary S. Stein1, Jane B. Lian1

1Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA

2Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA

3Prostate Cancer Discovery and Development Program, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA

Correspondence to:

Jane B. Lian, email: jane.lian@uvm.edu

Keywords: prostate cancer progression, AR, PTEN, TRAMP, miRNA targeting Runx

Received: August 04, 2016    Accepted: September 02, 2016    Published: September 13, 2016

ABSTRACT

While decades of research have identified molecular pathways inducing and promoting stages of prostate cancer malignancy, studies addressing dynamic changes of cancer-related regulatory factors in a prostate tumor progression model are limited. Using the TRAMP mouse model of human prostate cancer, we address mechanisms of deregulation for the cancer-associated transcription factors, Runx1 and Runx2 by identifying microRNAs with reciprocal expression changes at six time points during 33 weeks of tumorigenesis. We molecularly define transition stages from PIN lesions to hyperplasia/neoplasia and progression to adenocarcinoma by temporal changes in expression of human prostate cancer markers, including the androgen receptor and tumor suppressors, Nkx3.1 and PTEN. Concomitant activation of PTEN, AR, and Runx factors occurs at early stages. At late stages, PTEN and AR are downregulated, while Runx1 and Runx2 remain elevated. Loss of Runx-targeting microRNAs, miR-23b-5p, miR-139-5p, miR-205-5p, miR-221-3p, miR-375-3p, miR-382-5p, and miR-384-5p, contribute to aberrant Runx expression in prostate tumors. Our studies reveal a Runx/miRNA interaction axis centered on PTEN-PI3K-AKT signaling. This regulatory network translates to mechanistic understanding of prostate tumorigenesis that can be developed for diagnosis and directed therapy.


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