Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients

Abstract

Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration‐resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function of PCDHB9, which encodes the protocadherin B9 protein. Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT‐PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9‐mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance. Results The qRT‐PCR revealed that the expression of PCDHB9 was much higher in PCa than that in non‐neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan‐Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50 value of PCDHB9 siRNA‐transfected PCa cells was significantly lower than that of negative control siRNA‐transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival. Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.

Retracted Article: Long noncoding RNA PCA3 regulates glycolysis, viability and apoptosis by mediating the miR-1/CDK4 axis in prostate cancer

“…34 More particularly, CDK4 was involved in the regulatory pathway which mediated cell cycle, apoptosis, proliferation, migration, invasion and tumor growth in prostate cancer. 20 In our study, we found that CDK4 was increased and regulated by PCA3 and miR-1 in prostate cancer, revealing the promising regulatory network of PCA3/miR-1/CDK4 in prostate cancer progression. However, there was absence of the direct role of CDK4 in glycolysis, viability and apoptosis of prostate cancer cells.…”

“…19 Notably, CDK4 has an impact on prostate cancer progression by regulating cell cycle, apoptosis, proliferation, migration and invasion. 20 Hence, we hypothesized the PCA3/miR-1/CDK4 network might play a pivotal role in progression of prostate cancer. In the present study, we rst measured the expressions of PCA3, miR-1 and CDK4 in prostate cancer tissues and cells.…”

Protocadherins at the Crossroad of Signaling Pathways

“…Neuronal apoptosis is induced by ncPcdh overexpression or cPcdh loss. In oncogenesis, most Pcdhs seem to have a tumor suppressor function, as for several cancer types their downregulation [with the exception of PCDHB9 (Mukai et al, 2017;Sekino et al, 2019), and PCDH9 (Robbins et al, 2018)] correlates with tumor survival. Taken together, the precise dosage control of Pcdhs might therefore be crucial for cell survival in different contexts.…”

TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma

“…Immunohistochemistry was performed as described previously [15]. Sections were incubated with anti-TUBB3 antibody (1:100; BioLegend, San Diego, CA, USA), anti-CD44 antibody (1:100; H-CAM; clone DF1485; Novocastra, Newcastle, UK), anti-CD133 antibody (1:100; clone AC133; Miltenyi Biotec, Auburn, CA, USA), anti-p53 antibody (1:50; clone DO-7; DakoCytomation, Glostrup, Denmark), and anti-PD-L1 antibody (1:300; ab205921; clone 28-8; Abcam) for 1 h at room temperature.…”