Abstract
BackgroundThis study aimed to preliminarily assess the relationship between erythropoietin‐producing hepatocellular carcinoma receptor A3 (EphA3) and androgen receptor (AR) protein expression levels and prognosis in prostate cancer (PCa) to better understand the role of EphA3 in the prognosis and progression of PCa.MaterialsWe investigated the expression of EphA3 and AR in human PCa by immunohistochemistry.ResultsEphA3 and AR were both significantly upregulated in PCa, with expression mainly localized to the nucleus. A high level of AR expression was found in 48.4% of 64 tumor samples, which was significantly more than in the adjacent tissue samples (15.6%) (P < 0.01). The percentage of samples expressing a high level of EphA3 was significantly greater in the PCa samples (54.7%) than in the adjacent tissue samples (20.3%) for the 64 tumors (P < 0.01). The high levels of EphA3 and AR expression in the PCa tissue samples were both correlated with the pathological stage, bladder and rectal invasion, distant metastasis, and preoperative PSA level (both P < 0.05). The survival time was significantly shorter in high levels of AR expression of patients. (P < 0.01). A high level of EphA3 in PCa patients suggests a poor prognosis (P < 0.05). Biochemical recurrence, distant metastasis, and the final scores of EphA3 and AR expression were significantly correlated with the prognosis of PCa (P < 0.05).ConclusionsIncreased EphA3 expression is an independent prognostic factor for a poor outcome and decreased survival in PCa.
Highlights
Prostate cancer (PCa) represents the highest proportion of new cancer cases and has the second highest mortality rate in males according to the latest cancer statistics by the American Cancer Society.[1]
Positive staining of the andro‐ gen receptor (AR) protein was found in the nucleus, erythropoietin‐producing hepatocellular carcinoma receptor A3 (EphA3) was located in the nucleus and cytoplasm of the prostate cancer (PCa) tissues, and the adjacent normal prostate tissues all showed faint staining according to the IHC of successive tumor tissue sections (Figure 1)
The same phenomenon regarding EphA3 expression was re‐ ported by Wu et al,[22] who showed using a human PCa tissue microar‐ ray that EphA3 is overexpressed in PCa specimens and that EphA3 is highly expressed in androgen‐independent and metastatic cell lines
Summary
| 2 of 7 plays an vital role in the male phenotype and PCa biology. PCa was originally identified as an androgen‐dependent tumor, and its growth and survival were found to be controlled by AR signal‐ ing.[4]. The mRNA level of EphA3 differs significantly (192‐fold) between androgen‐independent PCa and androgen‐dependent PCa cell lines according to a DNA methyl‐ ation chip‐based study.[7] Our previous data showing that the EphA3 gene is AR‐regulated and contains an AR genomic binding site was obtained using chromatin immunoprecipitation (ChIP) in combina‐ tion with direct sequencing (ChIP‐seq). Singh et al demonstrated that EphA3 is significantly upregulated in castration‐resistant PCa cells, which exhibit differential expression during androgen‐inde‐ pendent progression.[8] These results prompted the present study focusing on the correlation between EphA3 and AR in the malignant behavior of PCa. Eph receptors (Ephs) are the largest family of receptor tyrosine kinases with fourteen receptors divided into two subfamilies (EphAs and EphBs); these receptors are associated with angiogenesis and tumor vasculature in various human cancers.[9] EphA3 is highly ex‐ pressed in the brain, kidneys, heart, and lungs during embryonic development and declines to a low level in adults. We attempted to preliminarily assess the relationship between EphA3 and AR protein expression levels in PCa and evalu‐ ated the prognostic impact of EphA3 to better understand the role of EphA3 in the progression and prognosis of PCa
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