ABSTRACT
Many prostate cancer (PCa) patients die of recurrent disease due to the emergence of hormone-independent cancer cells of which the mechanism is not fully understood. Our previous studies demonstrated that most castration- resistant prostate cancers (CRPC) overexpress the HOXB13 transcription factor to confer positive growth signals. Since HOXB13 also suppresses p21WAF1/CIP1 (p21) expression, we studied the correlation between HOXB13 and p21 in selected samples of PCa. While there was no statistically significant correlation between expression of HOXB13 and p21, HOXB13-deficient tumors had three times higher odds for expressing p21 than HOXB13-positive tumors. Moreover, CRPC showed more negative correlation than hormone-dependent PCa (HDPC). Further in vitro proliferation assay demonstrated that androgen did not affect the growth-suppressive function of p21 in androgen-dependent PCa cells, suggesting that p21 seems to override the growth-promoting function of androgen and suppression of p21 expression by HOXB13 is an important step in PCa cell survival under no androgen influence. HOXB13 also inhibited AP-1 signals via suppressed expression of JNK/c-Jun. While HOXB13 suppressed p21 expression via regulation of JNK signals, alteration of p21 expression also affected c-Jun and AP-1 activity. Taken together, overexpression of HOXB13 in CRPC is an important step in avoiding the growth-suppressive effect of p21 in a harsh condition such as an androgen-deprived environment.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Homeodomain Proteins/metabolism , Prostatic Neoplasms/metabolism , Aged , Aged, 80 and over , Androgens/pharmacology , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Signaling System , Male , Middle Aged , Prostatic Neoplasms/pathologyABSTRACT
Many patients with prostate cancer have disease recurrence following surgical removal of tumors and fail to respond to androgen ablation therapy. Despite the existence of a number of clinical/pathological factors, it is not possible to predict which patients will fall into this category. The results of our previous studies demonstrated that the HOXB13 homeodomain protein plays a key role in the development of prostate cancer and the progression of this malignancy. In addition, HOXB13 has been reported to predict estrogen-resistant breast cancer tumors. The purpose of this study was to investigate whether HOXB13 could be used as a molecular marker to predict prostate cancer recurrence. To examine the role of HOXB13 as a molecular marker with clinical/pathological data, the expression of HOXB13 was compared using immunohistochemistry in 57 organ-confined prostate cancer tumors obtained by radical prostatectomy. There was no significant correlation between the expression of HOXB13 and most clinical/pathological parameters, including tumor margin, invasion, pathological stage and risk level. The HOXB13 expression levels correlated with the Gleason score and there was a positive correlation with the pre-operative prostate specific antigen (PSA) levels. Accordingly, the tumor specimens from 4 patients who ultimately had biochemical failure (PSA >0.2 ng/ml), all showed a high expression of HOXB13, while their risk levels were either intermediate or high. This is the first study to report that HOXB13, together with other clinical/pathological factors, can be used as a molecular marker to predict the progression of prostate cancer.
