PgmNr M5089: GNL3 modulates prostate cancer metastasis susceptibility.

Authors:
M. Lee 1 ; K. A. Williams 1 ; Y. Hu 2 ; J. Andreas 1 ; S. J. Patel 1 ; S. Zhang 3 ; N. P. S. Crawford 1

Institutes
1) Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD 20892, USA; 2) Center for Biomedical Informatics and Information Technology, NCI, NIH, Rockville, MD 20850, USA; 3) Computational and Statistical Genomics Branch, NHGRI, NIH, Bethesda, MD 20892, USA.

Abstract:

Prostate cancer is the second leading cause of cancer mortality in men in developed countries. However, the molecular determinants of prostate cancer metastasis remain unclear. Previously, we reported that germline variation influences metastasis in the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of prostate cancer. These mice develop prostate tumors similar to a subset of poor outcome, treatment-associated human prostate cancer tumors. Germline variation introduced by PWK/PhJ caused significant suppression of tumor formation and metastases in the (TRAMP x PWK/PhJ) F1 males. GNL3, which encodes for a binding partner of p53 and functions in cell cycle regulation, was identified as a novel candidate metastasis susceptibility gene through a systems genetics approach using 201 (TRAMP x PWK/PhJ) F2 males and multiple prostate cancer patient datasets. Quantitative trait locus (QTL) mapping identified a locus on Chromosome 14 (LOD = 4.41; genome-wide P = 0.032) encompassing Gnl3 to be associated with distant metastasis-free survival. In two prostate cancer patient datasets, GNL3 expression was associated with an increased risk of aggressive disease and poorer disease-free survival. In addition, GNL3 harbored SNPs associated with aggressive tumorigenesis in the PLCO/CGEMS GWAS of 1,172 prostate cancer patients. Here, we aim to examine the molecular mechanisms of GNL3 as a metastasis susceptibility modifier using human prostate cancer cell lines PC-3 and LNCaP stably over-expressing GNL3. Over-expression of GNL3 in PC-3 caused an increase in cell proliferation and decreased in vitro cell migration and invasion compared to control cells. In soft agar assays, over-expression of GNL3 in both PC-3 and LNCaP cells increased colony count. Subcutaneous injections into the flanks of NU/J male mice of GNL3 over-expressing PC-3 cells, but not LNCaP cells, caused a significant increase in tumor burden compared to control. Pathway analysis of microarray data from cells over-expressing GNL3 demonstrated that over-expression of GNL3 modulates cell cycle regulators. These results collectively demonstrate a role for GNL3 in modulating metastasis susceptibility possibly by regulating cell cycle-related gene expression. This study, in addition to our previous studies, continues to exemplify how mouse models can be used to identify metastasis susceptibility genes through a novel systems genetics approach, and gives new insight into the molecular mechanisms of fatal prostate cancer.