Abstract
Prostate cancer (PC) is one of the most common solid tumors in men. However, the molecular mechanism of PC remains unclear. Numerous studies have demonstrated that long noncoding RNA (lncRNA) can act as microRNA (miRNA) sponge, one type of competing endogenous RNAs (ceRNAs), which offers a novel viewpoint to elucidate the mechanisms of PC. Here, we proposed an integrative systems biology approach to infer the gain and loss of ceRNAs in PC. First, we re-annotated exon microarray data to obtain lncRNA expression profiles of PC. Second, by integrating mRNA and miRNA expression, as well as miRNA targets, we constructed lncRNA-miRNA-mRNA ceRNA networks in cancer and normal samples. The lncRNAs in these two ceRNA networks tended to have a longer transcript length and cover more exons than the lncRNAs not involved in ceRNA networks. Next, we further extracted the gain and loss ceRNA networks in PC. We found that the gain ceRNAs in PC participated in cell cycle, and the loss ceRNAs in PC were associated with metabolism. We also identified potential prognostic ceRNA pairs such as MALAT1-EGR2 and MEG3-AQP3. Finally, we inferred a novel mechanism of known drugs, such as cisplatin, for the treatment of PC through gain and loss ceRNA networks. The potential drugs such as 1,2,6-tri-O-galloyl-beta-D-glucopyranose (TGGP) could modulate lncRNA-mRNA competing relationships, which may uncover new strategy for treating PC. In summary, we systematically investigated the gain and loss of ceRNAs in PC, which may prove useful for identifying potential biomarkers and therapeutics for PC.
Highlights
Prostate cancer (PC) is the second most frequently diagnosed cancer and the six leading cause of cancer death in males worldwide [1]
We found that some long noncoding RNA (lncRNA) acting as miRNA sponges led to different physiological and pathological states in the two competing endogenous RNAs (ceRNAs) networks
We found that lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in the gain ceRNA network was a hub node, and this lncRNA was a known PC-related lncRNA that could up-regulate early growth response 2 (EGR2) expression in PC patients, a key step in the pathogenesis of PC
Summary
Prostate cancer (PC) is the second most frequently diagnosed cancer and the six leading cause of cancer death in males worldwide [1]. MicroRNAs (miRNAs) are small non-coding RNA molecules ~ 22 nucleotides in length, which are involved in RNA silencing and post-transcriptional regulation of gene expression [4]. MiRNAs play important roles in multiple biological processes, including cell development, metabolism, proliferation, differentiation and apoptosis [5, 6], and their expression has been associated with many diseases and can be altered by environmental factors, kinase and small molecule inhibitors [7, 8]. Many studies have found that mRNA can reduce miRNA bioavailability by inhibiting targeted mRNA expression, and acting as competing endogenous RNAs (ceRNAs) [9]. LncRNA H19-ZEB1 ceRNA pair has been demonstrated to regulate cell proliferation and migration in gastric cancer [15] and Yu et al have found that GAS5 acted as a ceRNA of miR-222 can increase p27 expression level, and inhibit liver fibrosis progression [16]. Previous reports have focused on the identification of lncRNAs in PC, the study of lncRNA as ceRNA in PC is still in its infancy
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