Translational perspectives on MSMB and CRISP3 expression and regulation in prostate cancer

Abstract: Prostate cancer is currently the most common form of cancer in Sweden. Currently, the only biomarker used in the clinic is serum PSA, and there is a great need for new biomarkers that may increase the diagnostic and prognostic information so that better predictions can be made, and treatment may be tailored. Here, we have investigated two proposed biomarkers microseminoprotein-β (MSMB) and cysteine-rich secretory protein-3 (CRISP3). Firstly, we wanted to validate previous findings, that MSMB and CRISP3 are predictors of recurrence in patients undergoing radical prostatectomy for localized prostate cancer. Using a novel automated image analysis tool, IHC-MARK, we found that MSMB was an independent predictor of recurrence in a large patient cohort. Further, we showed that expression of both MSMB and CRISP3 was induced by androgen in vitro, and MSMB was decreased in patients receiving androgen deprivation therapy prior to radical prostatectomy. MSMB was virtually lost in advanced prostate cancer, in contrast to CRISP3 which was highly expressed. Inflammation has been suggested to be a primary aetiological event in prostate cancer and the presence of putative binding elements for inflammatory transcription factors in the promoter region of CRISP3 led us to hypothesise that CRISP3 may be regulated by inflammatory stimuli. Instead, stimulation of prostate cancer cells with interleukin (IL)-6 strongly induced MSMB expression but had no effect on CRISP3 expression. A long-term IL-6 stimulated cell line, however, had no MSMB expression, probably due to DNA methylation. Finally, expression of MSMB in cell lines without endogenous MSMB resulted in decreased cyclin D1 expression and reduced proliferation. In conclusion, MSMB is an independent predictor of recurrence, whereas the value of CRISP3 as a biomarker remains to be elucidated. In vitro studies show that MSMB may be important for prostate cancer proliferation, but more studies on MSMB and CRISP3 functions are warranted.