Abstract
Docetaxel is the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients ultimately become refractory due to the development of docetaxel resistance. The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis including prostate cancer (PC). In this study, we investigated the transcriptional levels of 26 representative T-UCRs and determined the regions that were differentially expressed in PC. Quantitative real-time polymerase chain reaction analysis revealed that the expression of T-UCR Uc.63+ was increased in PC tissues. MTT assay and wound healing assay revealed that Uc.63+ was involved in cell growth and cell migration. miR-130b was predicted to have binding sites within the Uc.63+ sequence. The expression of miR-130b was significantly disturbed by the overexpression or knockdown of Uc.63+. We also showed that Uc.63+ regulated the expression of MMP2 via miR-130b regulation. Furthermore, overexpression of Uc.63+ increased the expression of AR and its downstream molecule PSA and promoted resistance to docetaxel through AR regulation. In patients treated with docetaxel, the expression of serum Uc.63+ in the docetaxel-resistant patients was higher than that in the docetaxel-sensitive patients (P = 0.011). Moreover, Kaplan-Meier analysis showed that the high expression of serum Uc.63+ correlated with a worse prognosis (P = 0.020). These results substantially support the important role that Uc.63+ plays in PC progression by interacting with miR-130b and indicate that Uc.63+ could potentially be a promising serum marker for deciding the best treatment for patients with CRPC.
Highlights
Prostate cancer (PC) is the most prevalent cancer among men and the second leading cause of cancer-related death in developed countries [1]
To validate the results obtained by a microarray analysis, we examined the expression of these 26 transcribed ultraconserved regions (T-UCRs) by quantitative real-time polymerase chain reaction using 12 prostate cancer (PC) tissues and 8 non-neoplastic prostate tissues (Supplementary Figure 1)
To further investigate the usefulness of Uc.63+ as a serum biomarker for PC, we examined the expression of Uc.63+ in the serum of 10 patients with benign prostatic hyperplasia (BPH), 24 patients with primary PC, and 45 patients with metastatic PC by droplet digital PCR
Summary
Prostate cancer (PC) is the most prevalent cancer among men and the second leading cause of cancer-related death in developed countries [1]. Androgen receptor (AR) is largely involved in the development and growth of PC [2], and most patients with PC are initially sensitive to androgen deprivation therapy Most of these patients eventually develop castration-resistant PC (CRPC) (defined as disease progression during androgenablation therapy despite secondary hormone therapy) that will inevitably result in metastasis and death [3]. T-UCRs show a ubiquitous or a tissue-specific pattern and exhibit distinct profiles in various human cancers [11], and whether T-UCRs play an oncogenic role or a tumorsuppressive role depends on the cellular context [11], [12] Based on this evidence, T-UCRs could provide useful markers to classify the characteristics of human cancer, diagnostic markers for some specific types of cancer, and predictive markers for drug sensitivity or prognosis of cancer patients. We evaluated the expression of T-UCRs in PC, investigated their functional roles in PC progression and AR regulation, and analyzed the effect of Uc.63+ on docetaxel resistance
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