Original ArticlesIdentification of novel piRNAs in bladder cancer
Introduction
Bladder cancer is the most common cancer in the urinary system. In bladder cancer, transitional cell carcinoma (TCC) is the most predominant histopathological type, which accounts for up to 90% of all cases. The development of bladder cancer involves multi-factors and is a multi-stage process. It had been well-established that cigarette smoking and occupational and environmental exposures are risk factors for bladder cancer [1]. At present, researchers have mainly focused on investigating the effect of non-coding small regulatory RNAs, including microRNAs (miRNAs), endogenous small interfering RNAs (siRNAs), and PIWI-interacting RNAs (piRNAs). To date, the most widely studied non-coding small RNAs are miRNAs, which can regulate gene expression via binding to the sequence of target mRNAs [2], [3], [4]. Our previous findings found that miR-146a was associated with bladder cancer risk and prognosis [5]. Compared with miRNAs, piRNAs are far less investigated RNA molecules. Recently, piRNAs have emerged as important regulators in multiple species.
piRNAs are a class of non-coding small RNA of 24–30 nucleotides and are produced via a Dicer-independent mechanism and can bind to PIWI proteins to form complexes to induce a silencing effect [6], [7], [8], [9]. Studies in mice, Drosophila, Caenorhabditis elegans, and zebrafish have indicated that piRNAs play important roles in germline development [7], [8], [9], [10], [11], [12], [13]. However, the function of PIWI-piRNA complexes has yet not been fully understood. Some studies have suggested that piRNAs have a potential role in the regulation of transposable elements in the germline [14], [15], and the PIWI-piRNA complex has been shown to regulate histone modifications at the binding site [16]. Rajasethupathy et al. revealed that piRNAs are prevalently expressed in the brain and subsequently found that the PIWI–piRNA complex can regulate methylation of a CpG island in the promoter of CREB2 via a piRNA binding to the CREB2 transcript, thereby inducing enhanced long-term synaptic facilitation in Aplysia [17]. Taken together, piRNAs have a potential role in transposon silencing and the epigenetic and post-transcriptional regulation of gene expression [18].
piRNAs have been found to be involved in the development of cancer, such as cervical cancer [19], gastric cancer [20], [21], breast cancer [22], multiple myeloma [23], and hepatocellular carcinoma [24]. These findings indicated that piRNAs play important roles as oncogenes or tumor suppressor genes in carcinogenesis. In this study, we used a piRNA profile to explore the effects of piRNA in bladder cancer and identified a novel piRNA DQ594040 associated with bladder cancer (piRABC).
Section snippets
Patients and samples
Three bladder cancer tissues and their adjacent normal bladder tissues were examined in a piRNA microarray study. The clinical characteristics of three bladder cancer patients are shown in Supplementary Table S1. These fresh bladder tissue samples were collected from bladder cancer patients who underwent surgical resections at the Department of Urology, Jiangsu Province Hospital of TCM in 2010. All included patients were histologically confirmed to have bladder transitional cell carcinoma
piRNA microarray data analysis
Three pairs of bladder cancer tissues and their adjacent normal tissues were used to investigate the piRNAs associated with bladder carcinogenesis using a piRNA microarray, and the clinical characteristics of these three bladder cancer patients are shown in Supplementary Table S1. Raw piRNA data were extracted using Agilent Feature software. As shown in Fig. 1A, a box plot is a way to visualize the dataset distribution, which is used to compare the intensity distribution from the three paired
Discussion
Importantly, in 2006, three research groups identified that piRNAs associated with PIWI protein were highly abundant in the mouse testis [7], [8], [9]. Many studies have indicated that the effect of piRNA biogenesis can induce animal germline stem cell loss or sterility, which suggested that piRNAs have important roles in germline development [30], [31], [32]. Recently, piRNAs have been identified outside the germline or testis [17], [25] and in human cancer cells [19], [20], [21], [22], [24].
Conflict of interest
The authors have declared no conflicts of interest.
Funding
This study was partly supported by the National Natural Science Foundation of China (81473050, 81102089, and 81230068), Natural Science Foundation of Jiangsu Province (BK2011773 and BK2011775), the Key Program for Basic Research of Jiangsu Provincial Department of Education (11KJB330002, and 12KJA330002), Jiangsu Provincial Six Talent Peaks Project (2012-SWYY-028, 2012-WSN-30), Specialized Research Fund for the Doctoral Program of Higher Education (20123234110001), the research project of
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Haiyan Chu, Gaoyun Hui, Lin Yuan contributed equally to this work.