LncRNA, a group of RNAs that is described in 2002 for the first time, presents with several characteristics, including poor conservation, tissue specificity and so on [7, 18, 19]. LncRNAs exist in almost every branch of life and are involved various important biological activities such as genomic imprinting, cell differentiation and organogenesis [20, 21]. LncRNAs regulating gene expressions are mainly through three different ways: transcription regulation, post-transcription regulation or epigenetic regulation [22]. For transcription regulation, lncRNAs are able to regulate different transcription processes such as modulate transcription factor activity, mediate RNA polymerase (RNAP) II activity and regulate the functions of RNA binding protein. For post-transcription regulation, lncRNAs also modulate various post-transcriptional processes, such as splicing, editing, transport, translation and degradation. Besides, lncRNAs are also involved epigenetic regulations such as imprinting and X-chromosome inactivation by recruiting chromatin remodeling complexes to specific genomic loci [23, 24]. In recent years, the role of lncRNAs in a number of diseases have been intensively investigated, especially in complicated diseases such as cancers, CAD and autoimmune diseases [18]. Taken psoriasis as an example, a study explores the lncRNA expression profiles in skin sample of psoriasis patients, which identifies 1080 novel differentially expressed lncRNAs in psoriasis patients compared with controls, further analyses revealed that these dysregulated lncRNAs are mostly enriched in biosynthesis of unsaturated fatty acid and cytokine activity [25]. However, the implications of lncRNA expression profiles in PSA are still obscure.
PSA is a systemic inflammatory disease that both genetic and environmental factors play crucial roles in the etiology of this disease [5]. Since lncRNA expression profiles are reported to be paramount in etiopathologies of autoimmune diseases such as SLE, IBD and RA, exploring lncRNA expression profiles of PSA might also be able to provide new insights for PSA pathogenesis and find novel biomarkers for predicting PSA risk and activity [9,10,11]. Whereas relevant study is rarely found until now, with only one study reported [12]. In this previous study, lncRNA expression profiles in PBMC of 10 PSA patients are analyzed by microarray, which discovers 259 DELs in PSA patients compared with HCs, further analyses reveal that these DELs are implicated PSA-related signaling pathways such as immune response, glycolipid metabolism, bone remodeling and type 1 interferon. Subsequently, 7 lncRNAs (TRIM55–1, EPB41L4A-AS1, LINC00657, LINC00909, RP11-539 L10.3, LA16c-360H6.3 and LUCAT1) are selected for validation in 20 PSA patients and 20 HCs, which discloses that LA16c-360H6.3 is upregulated while the rest of 6 lncRNAs are downregulated in PSA patients compared with HCs [12]. However, this study uses microarray to detect DELs rather than RNA sequencing. What’s more, the sample size for validation is small, with only 20 samples in each group, which also decreases statistical power. Considering that no more studies are reported to explore the role of lncRNA expression profiles in PSA, and the potential pathways or mechanisms that lncRNA expression profiles might be involved are largely unelucidated, we conducted the current study by RNA sequencing, which discovered 130 DELs in PSA patients compared to NCs, among which 76 lncRNAs were upregulated while 54 lncRNAs were downregulated. The number of DELs in our study was smaller than the previous study, which might be due to the following reasons: (1) our study discarded those lncRNAs that were discovered in less than 50% samples, whereas the previous study does not. (2) Our study utilized RNA sequencing to detect DELs, while the reported study uses microarray to detect DELs, which might cause differences. (3) DELs in our study must meet an adjusted P value < 0.05 (BH adjusted method) and a fold change≥2.0, while BH adjusted method is not used in their study. Taken together, the DELs in the current study were relatively fewer than that of reported study. In addition, we compared our data-set with that previous study, discovering that 1 DEL and 41 DEMs in our data-set were overlapped with that previous study, indicating that the remaining 129 DELs and 292 DEMS in our study were first identified.
The enrichment analyses are prevalent approaches to illuminate the molecular functions, biological processes, cellular components and signaling pathways that differentially expressed genes might be implicated [26, 27]. In the current study, enrichment analyses disclosed that DELs and DEMs were mostly associated with nucleosome, extracellular exosome and extracellular matrix, and the top enriched pathways were SLE, alcoholism and viral carcinogenesis. The possible explanations for the results might be that: for nucleosome, it is reported that its loss contributes to macrophage activities, indicating that DELs involved PSA might be through regulating DEMs then affecting the numbers of nucleosome thereby activating macrophages [28]. For extracellular exosome, it is discovered to induce inflammatory immune response in a couple of autoimmune diseases such as SLE and RA, and extracellular exosome in PSA patients is able to stimulate osteoclast differentiation, suggesting that DELs implicated PSA might also be through regulating DEMs then modulating exosome thereby mediated osteoclast differentiation [29, 30]. For extracellular matrix, it serves important functions to cell adhesion, cell-to-cell communication and cell differentiation, and the dysregulated degradation of extracellular matrix is associated with a number of diseases such as osteoarthritis and PSA, therefore DELs involved PSA might also be through regulating DEMs then mediating degradation of extracellular matrix [31, 32]. For SLE, it closely correlates with autoimmunity and inflammation, which are similar to PSA. As for alcoholism and viral carcinogenesis, their associations with PSA need further investigation.
The disease manifestations of PSA are sometimes varied from patients to patients, which make the diagnosis difficult. To explore if there are DELs that could be served as biomarkers for disease risk, inflammation or activity of PSA, 3 top upregulated and 2 downregulated lncRNAs were selected and their expressions were validated in 93 PSA patients and 93 NCs by qPCR assay, which revealed that both lnc-RP11-701H24.7 and lnc-RNU12 expressions were increased in PSA patients compared with NCs, and they disclosed good predictive values for PSA risk with high AUCs. Besides, lnc-RP11-701H24.7 and lnc-RNU12 were also positively associated with inflammation level and disease activity of PSA. The possible reasons might be that: both lnc-RP11-701H24.7 and lnc-RNU12 might be implicated PSA development and progress through (i) epigenetic regulations such as histone and DNA methylation. (ii) Mediating gene transcription; (iii) regulating its target genes such as COL1A2, RNU12 and MAP1A. However, the in-depth mechanisms of lnc-RP11-701H24.7 and lnc-RNU12 being implicated PSA pathogenesis need further investigation [33]. In addition, we also observed that lnc-TRAV1–2 was negatively associated with PASI score and PGA score, indicating that lnc-TRAV1–2 might be also correlated with decreased disease activity of PSA. In short, it was the first study to discover specific lncRNAs that might be regarded as biomarkers for PSA risk and activity, which might remarkably promote the early diagnosis and contribute to discovering novel approaches for improving long-term outcomes of PSA patients.
There were some limitations in the current study. First, the study did not evaluate the treatment response of PSA patients, so the role of lncRNA expression profiles in treatment response and long-term outcome of PSA patients were not investigated. Second, most patients in this study were from East China, which might bring in selection bias. Third, although we discovered the positive correlations of lnc-RP11-701H24.7 and lnc-RNU12 with disease risk and activity, the detailed mechanisms of these two lncRNAs in development and progression of PSA remained unclear, which needed to be further explored in our future work.