Epithelial cell transcriptome of poorly and moderately differentiated prostate cancers
Authors: Syed Shaheduzzaman, Chun-Ling Gao, Zhining Wang, Bungo Furusato, Gyorgy Petrovics, Vasantha Srikantan, Lakshmi Ravindranath, Martin E. Nau, Yidong Chen, David G. McLeod, Isabell A. Sesterhenn, Maryanne Vahey, Shiv Srivastava
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

826 

Introduction: The focus of the current study is to identify prostate cancer (CaP) associated gene expression signatures in specific cell types of the human prostate gland with a goal to define molecular targets/pathways involved in CaP progression. Here we report gene expression features of poorly differentiated (PD) and well differentiated (WD) prostate cancer cells and matched benign prostate epithelial cells. Tumor cell specific gene expression features were defined focusing on genes differentiating PD and WD prostate tumor cells. Such molecular targets have potential to define prognostic markers and biochemical pathways involved in CaP progression. Methods: Laser capture micro-dissected (LCM) epithelial cells from benign and malignant prostate glands of carefully selected CaP patients were analyzed by 80 Affymetrix HG U133 Plus 2.0 GeneChips. As a follow-up of our earlier study, we have further evaluated the expression patterns in paired benign and cancer epithelial cells from two patient groups (20 patients per group), one with “high risk” (HR) CaP (poorly differentiated tumor cells, Gleason score 8-9, PSA recurrence) and the other with “moderate risk” (MR) CaP (well to moderately differentiated tumor cells, Gleason score 6-7, no PSA recurrence). Genes differentially expressed between benign and tumor epithelium of HR and MR groups were analyzed for biochemical pathways/networks. Results: Prostate tumor cell specific expression alterations of genes involved in cancer and inflammatory pathways were highlighted by various bio-informatics approaches. Several genes that were differentially altered in tumor cells of MR groups were part of cell morphology and cell death pathways. Huntington-interacting protein-1 (Hip-1) interactor (Hippi) associating with HR specimens was among genes noted in two independent GeneChip experiments from our group. Hippi has also been implicated in apoptosis pathway. We have further analyzed the expression of Hippi in tumor and benign epithelial cells of 96 CaP patients by QRT-PCR. Hippi significantly discriminated CaP in HR group (up-regulated) from MR group (down-regulated). In addition, statistical analysis revealed a significant correlation of Hippi expression with Gleason sum (ANOVA, p=0.0006) and pathological T stage (T-test, p=0.0243). Conclusion: Our study defines gene expression signatures in benign and malignant prostate tissues that have potential to distinguish CaP with moderate and high risk progression. HIPPI , exhibited similar expression patterns in both GeneChip and QRT-PCR assays. The HIPPI protein interacts with HIP1, that was previously reported to be overexpressed in CaP with poor prognosis. Further evaluations of HR associated gene expression signatures have potential to define functional targets/pathways involved in CaP progression.