Abstract 1079: PCDH7 is overexpressed in advanced prostate cancer and modulates aggressive phenotype in prostate cancer cells

Abstract

Abstract Introduction: Most of prostate cancer (PCa) deaths are a result of distant metastasis and due to emergence of castrate resistant PCa (CRPC). Protocadherins (PCDHs) are members of the cadherin superfamily that regulate cell adhesion. Their extracellular domains contain cadherin-like repeats, but they differ significantly from classical cadherins with respect to their unique cytoplasmic domains that lack the conserved motifs for binding β-catenin and p120-catenin. PCDH7, a cadherin superfamily transmembrane protein that is known to function in cell-cell recognition and adhesion, is reported to be overexpressed in breast cancer and non-small cell lung cancer and promoted tumor metastasis. The role of PCDH7 in PCa is investigated for the first time in the present investigation. Materials and Methods: PCa cells- LNCaP, C4-2b, DU145, PC3, 22Rv1 and RWPE1 were used in this study. PCDH7 protein and mRNA levels were checked by Western Blotting and quantitative real time PCR respectively. Immunohistochemistry was done to check expression in TRAMP mice FFPE prostate tissue sections and human prostate tissues. Publically available data set (Trento 2016) was used to analyze PCDH7 expression in NEPC patients. PCDH7 lentiviral knock down was performed using PCDH7 shRNA in PC3 cells. Cell migration and invasion were done using IncuCyte® Scratch Wound Cell Migration and Invasion System. Colony formation was assessed by staining with 0.4% crystal violet after 3 weeks of cell seeding. Results: PCDH7 mRNA and protein is overexpressed in CRPC cells (C4-2b, 22Rv1, DU145 and PC3 cells as compared to castrations sensitive LNCaP cells as well as normal prostate RWPE1 cells. We observed highest levels for PCDH7 in enzalutamide refractory 22Rv1 cells. We also observed a significant increased expression of PCDH7 during tumor progression (30wk vs 12wk) in prostate tissues of TRAMP mice. Our results also show that PCDH7 is amplified in 9% of PCa patients and overexpressed in 43% patients. Immunohistochemical analysis of PCDH7 revealed high expression of PCDH7 in human prostate cancer tissues. EGF treatment enhanced ERK and AKT activities in time-dependent manner and the phosphorylation remain sustained even at late time points in PCDH7 positive PC3 cells as compared to decline in phosphorylation PCDH7 negative RWPE1 cells. shRNA-mediated knockdown of PCDH7 reduced ERK and AKT activities. Knockdown of PCDH7 also resulted in decreased cell migration, reduced cell invasion, and decreased colony formation. Collectively, these data suggest PCDH7 plays a crucial role in advanced PCa. Conclusion: Our results are the first direct demonstration of PCDH7 expression in PCa. Our exciting observations reveal a critical role for PCDH7 in prostate cancer progression. These results suggest that PCDH7 may be an attractive target for therapeutic intervention in PCa, in general, and CRPC in particular. Citation Format: Gauri Shishodia, Prakash Srinivasan Shanmugam, Sweaty Koul, Hari Koul. PCDH7 is overexpressed in advanced prostate cancer and modulates aggressive phenotype in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1079.