Abstract
The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5′ to 3′ polarity or 3′ poly (A), play an important role in multiple diseases. However, the potential roles of androgen-responsive circRNAs in prostate cancer remain unclear. In this study, we identified 3237 androgen-responsive circRNAs and 1954 androgen-responsive mRNAs after dihydrotestosterone (DHT) stimulation using microarray. Among them, the expression of 1296 androgen-responsive circRNAs was consistent with that of their parent genes, and we thought AR might regulate the expression of these circRNAs at the transcriptional level. In addition, 1941 circRNAs expression was not consistent with their parent genes, and we speculated that AR may regulate the expression of those circRNAs at the posttranscriptional level through affecting alternative splicing. Analyzing the androgen-responsive circRNAs regulated at the posttranscriptional level, we identified two key RNA binding proteins (RBPs), WTAP and TNRC6, using the circInteractome database, which may play important role in the biogenesis of androgen-responsive circRNAs. Furthermore, we explored the potential biological functions and predicted the molecular mechanisms of two dysregulated circRNAs (circNFIA and circZNF561) in prostate cancer. In this study, we revealed that circNFIA was upregulated in prostate cancer tissues and plasma samples from patients with prostate cancer; circNFIA may play an oncogenic role in prostate cancer. In contrast, circZNF561 was downregulated and may act as a tumor suppressor in prostate cancer. Our results suggest that androgen-responsive circRNAs might regulate the progression of prostate cancer and could be novel diagnostic biomarkers.
Highlights
Prostate cancer is the second most frequently diagnosed cancer in men worldwide, and 1.4 million estimated cases were diagnosed in 2020 [1]
We identified a set of androgen-responsive circRNAs and two important regulatory factors, WTAP and TNRC6, which may involve in circRNA biogenesis
We explored the potential biological functions and predicted the molecular mechanism of two androgen-responsive circRNAs, which may act as promising biomarkers for the diagnosis and treatment of prostate cancer
Summary
Prostate cancer is the second most frequently diagnosed cancer in men worldwide, and 1.4 million estimated cases were diagnosed in 2020 [1]. The incidence rates of prostate cancer increased in most countries, such as Sweden, Thailand, China, and Lithuania [2]. Androgen deprivation therapy (ADT) is the main treatment for advanced and metastatic prostate cancer [4]. Almost all patients develop castration-resistant prostate cancer (CRPC) approximately 2–3 years after ADT, at which time, the serum PSA levels increase again and the disease rapidly worsens [5,6]. The androgen receptor (AR) signaling pathway plays a vital role in the diagnosis and treatment of prostate cancer. CRPC, previously defined as hormone-independent prostate cancer, is known to still be androgen dependent. Understanding the role of the AR signaling pathway in the progression of prostate cancer is important to develop future therapies
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