Skp2 associates with Slug, androgen receptor and extracellular matrix proteins in patients with advanced prostate cancer

Background: The Skp2 F-box protein is the substrate recruiting component of the SCF (Skp1-Cullin 1-F-box) type of E3 ubiqutin-ligase complexes. Skp2 plays important role in prostate tumorigenesis which needs further elucidation.

Material and Methods: Prostate cancer patients cohort (N=101) was analyzed by immunohistochemistry for the following proteins (Skp2, AR, Ki-67, Slug, E-cadherin, beta-catenin, CTHRC1, periostin and versican) and statistically evaluated with clinico-pathological parameters. Coexpression study was performed using Opal Multiplex method.

Results: High Gleason score (>8, N=30) was significantly associated with higher nuclear Skp2 and lower E-cadherin expression (p<0.001 and 0.011, respectively) and with a trend for higher androgen receptor (p=0.062). Patients with metastasis in lymph nodes (N=29) had lower E-cadherin and cytoplasmic Skp2, (p<0.001 and 0.018, respectively), while nuclear Skp2, Slug (both nuclear and cytoplasmic), Ki-67 and androgen receptor showed a trend (p=0.176, 0.103, 0.032, 0.079 and 0.12, respectively) towards higher expression in the prostate cancer cells. Similar changes of the mentioned proteins were observed also in risk categorization (based on serum PSA, pT classification and Gleason score).

Nuclear Skp2 slightly correlated with AR, periostin, versican and CTHRC1 in the whole patients cohort (Rs 0.37, 0.34, 0.21 and 0.35, respectively). In patients with high Gleason score, nuclear Skp2 potently correlated with AR, and nuclear Slug (Rs 0.53 and 0.56, respectively). In patients with metastasis into lymph nodes, nuclear Skp2 similarly correlated with nuclear Slug and AR (Rs 0.56 and 0.37, respectively) while androgen receptor further correlated with Ki-67 (Rs 0.50). Althoulgh basal expression of Slug and Skp2 colocalized in the same cells, their increased expressions were mutually exclusive.

Conclusions: Skp2 correlates with androgen receptor, CTHRC1, periostin, versican and Slug which might contribute to agressive prostate cancer. Further mechanistical elucidation and clinical validation is needed.

Acknowledgements: This work was supported in part by grants NT13573 from the Czech Ministry of Health and NPU I LO1304 from the Czech Ministry of Education.

No conflict of interest.