Introduction

Hippo pathway regulates tissue homeostasis, organ size, and tumorigenesis. Here we investigated the expression of Hippo pathway proteins in docetaxel- and castration-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent radical prostatectomy (RP) with and without neoadjuvant chemohormonal therapy.

Methods

Docetaxel-resistant subline (22Rv-1-DR) was generated and confirmed the expression of Hippo pathway-related proteins including YAP, p-YAP, TAZ, and MOB4A. A tissue microarray with 210 cores from 70 high-risk localized PCa patients who underwent RP without neoadjuvant therapy (NNA), with neoadjuvant hormonal therapy (NHT), or with neoadjuvant chemohormonal therapy with docetaxel (CHT) was used to assess the nuclear and cytoplasmic expression of YAP and MOB4A in cancer cells. Expression levels among the three groups were statistically analyzed. Multivariate analyses were performed to investigate the prognostic factors of biochemical recurrence (BCR) in patients who underwent surgery with CHT.

Results

The expressions of nuclear YAP (nYAP) and nuclear p-YAP were markedly higher in 22Rv-1-DR cells than those in parental 22Rv-1.Cytoplasmic MOB-4A was down-regulated in 22Rv-1-DR cells. In human PCa tissues, YAP was expressed both in the nucleus and the cytoplasm, whereas MOB4A was mainly expressed in the cytoplasm. There was no difference in the mean nYAP intensity score in cancer cells between the NNA and NHT groups, whereas the mean nYAP intensity score was significantly higher in the CHT group than in the NHT groups (p = 0.034). The patients with a high nYAP intensity score in residual cancer cells after CHT had a significantly higher BCR rate than those with a low nuclear immunoreactivity score (p = 0.033). On multivariate analysis, preoperative PSA level and high nYAP intensity score were independent prognostic factors for BCR in patients with PCa treated with CHT.

Conclusions

nYAP expression in residual cancer cells is a potential prognostic marker for BCR in high-risk PCa patients who underwent RP after neoadjuvant chemohormonal therapy. The Hippo pathway may play an important role in chemohormonal resistance in patients with PCa.

Funding

None