Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non‐coding RNAs in T cells

Non‐coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell‐mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.     

Long non-coding RNAs in retinoblastoma

Retinoblastoma represents 3% of all childhood cancers and is the most common intraocular malignant tumor with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have reported new insights into the mechanism of retinoblastoma development, the involvement of regulatory non-coding RNAs remains unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidence has shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration, and invasion. Several lncRNAs, including BANCR, AFAP1-AS1, NEAT1, XIST, ANRIL, PlncRNA-1, HOTAIR, PANDAR, DANCR, and THOR, promote the progression and metastasis of retinoblastoma. However, some lncRNAs, such as MEG3, MT1JP, and H19, play a tumor suppressive role. Our review summarizes the functional role of lncRNAs in retinoblastoma and their potential clinical applications for diagnosis, prognosis, and treatment.     

Non-coding RNA-based regulation of inflammation

Inflammation is a multifactorial process and various biological mechanisms and pathways participate in its development. The presence of inflammation is involved in pathogenesis of different diseases such as diabetes mellitus, cardiovascular diseases and even, cancer. Non-coding RNAs (ncRNAs) comprise large part of transcribed genome and their critical function in physiological and pathological conditions has been confirmed. The present review focuses on miRNAs, lncRNAs and circRNAs as ncRNAs and their potential functions in inflammation regulation and resolution. Pro-inflammatory and anti-inflammatory factors are regulated by miRNAs via binding to 3'-UTR or indirectly via affecting other pathways such as SIRT1 and NF-κB. LncRNAs display a similar function and they can also affect miRNAs via sponging in regulating levels of cytokines. CircRNAs mainly affect miRNAs and reduce their expression in regulating cytokine levels. Notably, exosomal ncRNAs have shown capacity in inflammation resolution. In addition to pre-clinical studies, clinical trials have examined role of ncRNAs in inflammation-mediated disease pathogenesis and cytokine regulation. The therapeutic targeting of ncRNAs using drugs and nucleic acids have been analyzed to reduce inflammation in disease therapy. Therefore, ncRNAs can serve as diagnostic, prognostic and therapeutic targets in inflammation-related diseases in pre-clinical and clinical backgrounds.     

Role of non‐coding RNAs in pancreatic beta‐cell development and physiology

The progression of diabetes is accompanied by increasing demand to the beta‐cells to produce and secrete more insulin, requiring complex beta‐cell adaptations. Functionally active and ubiquitous non‐coding RNAs (ncRNAs) have the capacity to take part in such adaptations as they have been shown to be key regulatory molecules in various biological processes. In the pancreatic islets, the function of ncRNAs and their contribution to disease development is beginning to be understood. Here, we review the different classes of ncRNAs, such as long non‐coding RNAs (lncRNAs) and microRNAs (miRNAs), and their potential contribution to insulin secretion. A special focus will be on miRNAs and their regulatory function in beta‐cell physiology and insulin exocytosis. As important players in gene regulation, ncRNAs have huge potential in opening innovative therapeutic avenues against diabetes and associated complications.     

Non-coding RNAs regulate the BMP/Smad pathway during osteogenic differentiation of stem cells

MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the regulation of bone metabolism. The BMP/Smad pathway is a key signaling pathway for classical regulation of osteogenic differentiation. Non-coding RNAs (ncRNAs) and the BMP/Smad pathway both have important roles for osteogenic differentiation of stem cells, bone regeneration, and development of bone diseases. There is increasing evidence that ncRNAs interact with the BMP/Smad pathway to regulate not only osteogenic differentiation of stem cells but also progression of bone diseases, such as osteoporosis (OP), myeloma, and osteonecrosis of the femoral head (ONFH), by controlling the expression of bone disease-related genes. Therefore, ncRNAs that interact with BMP/Smad pathway molecules are potential targets for bone regeneration as well as bone disease diagnosis, prevention, and treatment. However, despite extensive studies on ncRNAs associated with the BMP/Smad pathway and osteogenic differentiation of stem cells, there is a lack of comparability. Moreover, some bone disease-associated ncRNAs with low abundance can be difficult to detect and there is a lack of mature delivery systems for their stable translocation to target sites, thus limiting their application. In this review, we summarize the research progress on interactions between ncRNAs and the BMP/Smad pathway during osteogenic differentiation of various stem cells and in the regulation of bone regeneration and bone diseases.     

Long noncoding RNA LINC00173 is downregulated in cervical cancer and inhibits cell proliferation and invasion by modulating the miR-182-5p/FBXW7 axis

Accumulating evidence has supported the concept that long noncoding RNAs (lncRNAs) participate in the initiation and progression of human cervical cancer (CC). The long intergenic nonprotein-coding RNA 173 (LINC00173) is a recently identified cancer-associated factor. However, the expression and biological role of LINC00173 in CC are poorly understood. Here, for the first time, we found that the expression of LINC00173 was decreased in CC tissues compared with that in nontumor tissues. Data from The Cancer Genome Atlas (TCGA) further revealed that the downregulated expression of LINC00173 in CC tissues was correlated with poor survival. Functionally, LINC00173 overexpression suppressed HeLa cell proliferation via induction of G0/G1 phase arrest. Ectopic expression of LINC00173 also repressed the invasiveness of HeLa cells. Conversely, LINC00173 depletion resulted in the enhanced proliferation and invasiveness of C33A cells. Mechanistically, LINC00173 functioned as a molecular sponge for miR-182-5p and inversely regulated the miR-182-5p level in CC cells. F-box and WD repeat domain-containing 7 (FBXW7) was identified as the target of miR-182-5p. LINC00173 overexpression enhanced the FBXW7 level via regulation of miR-182-5p in HeLa Cells. More importantly, the inhibitory effects of LINC00173 on HeLa cell proliferation and invasiveness were reversed by FBXW7 silencing. Taken together, the results indicate that the LINC00173/miR-182-5p/FBXW7 axis is critical for CC progression, which might offer new insights into effective therapy for CC.     

Seminal plasma microRNAs: potential biomarkers for spermatogenesis status

MicroRNAs (miRNAs) are small non-coding RNAs (18-25 nt), playing important regulatory roles via interaction with cellular messenger RNAs. The altered expression of miRNAs in specific tissues has been associated with diseases such as cancer and diabetes. We examined the presence of two selected miRNAs (miR-19b and let-7a) in human seminal plasma from fertile men and idiopathic infertile patients with oligozoospermia and non-obstructive azoospermia (NOA) using quantitative real-time PCR. We detected miRNAs in the seminal plasma of humans. The levels of miRNAs in the seminal plasma were reproducible in repeat samples from the same individuals. In addition, we examined the expression patterns of two selected miRNAs in 96 idiopathic infertile males (48 oligozoospermia and 48 NOA) and 48 fertile controls. Another 48 individuals of each group were used for verification. Our data showed that the expression levels of these two miRNAs in the seminal plasma significantly increased in idiopathic infertile males with NOA compared with fertile controls, whereas the expression levels were similar between idiopathic infertile males with oligozoospermia and fertile controls. In conclusion our results indicate that the expression of miR-19b and let-7a in the seminal plasma are reproducible and stable. Aberrant over-expression levels of miR-19b and let-7a may be an indicator of spermatogenic failure.     

Regulatory noncoding RNAs and the major histocompatibility complex

The Major Histocompatibility Complex (MHC) is a 4 Mbp genomic region located on the short arm of chromosome 6. The MHC region contains many key immune-related genes such as Human Leukocyte Antigens (HLAs). There has been a growing realization that, apart from MHC encoded proteins, RNAs derived from noncoding regions of the MHC—specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)—play a significant role in cellular regulation. Furthermore, regulatory noncoding RNAs (ncRNAs) derived from other parts of the genome fine-tune the expression of many immune-related MHC proteins. Although the field of ncRNAs of the MHC is a research area that is still in its infancy, ncRNA regulation of MHC genes has already been shown to be vital for immune function, healthy pregnancy and cellular homeostasis. Dysregulation of this intricate network of ncRNAs can lead to serious perturbations in homeostasis and subsequent disease.     

LINC00205 promotes proliferation,migration and invasion of HCC cells by targeting miR-122-5p

Long non-coding RNAs (lncRNAs) have been identified as crucial regulators in the tumorigenesis and progression of hepatocellular carcinoma (HCC). Recently, long intergenic non-protein coding RNA 205 (LINC00205) has been identified as a prognostic biomarker in HCC. However, the biological role of LINC0205 and its potential molecular mechanism are poorly investigated. Here, we found that the expression of LINC00205 was dramatically up-regulated in HCC tissues compared to adjacent nontumor tissues. Furthermore, the level of LINC00205 in both Hep3B and Huh7 cells was prominently higher than that in normal hepatic cell line LO2. Notably, the high expression of LINC00205 was strongly correlated with tumor size ≥5 cm, venous infiltration and advanced tumor stages. Functionally, LINC00205 knockdown obviously repressed the proliferation, migration and invasion of Hep3B and Huh7 cells in vitro. An inverse correlation between LINC00205 and miR-122-5p was detected in HCC tissues. Interestingly, LINC00205 knockdown increased the level of miR-122-5p in both Hep3B and Huh7 cells. Mechanistically, luciferase reporter assay demonstrated LINC00205 acted as a competing endogenous RNA (ceRNA) by directly interacting with miR-122-5p. More importantly, miR-122-5p overexpression significantly restrained the proliferation, migration and invasion of HCC cells. Collectively, our study provides solid evidence to support the oncogenic role of LINC00205 in HCC, which may be benefit for the improvement of HCC therapy.     

Non-coding RNAs: Regulators of glioma cell epithelial-mesenchymal transformation

GBM (glioblastoma multiforme) is the most malignant form of glioma and is the most commonly occurring primary malignant brain tumour. GBM is difficult to completely excise, resulting in an extremely high recurrence rate. The occurrence of an aggressive glioma phenotype depends on EMT (epithelial-mesenchymal transformation), in which epithelial cells transform into mesenchymal cells by losing their cell-cell adhesion and polarity. NcRNAs (non-coding RNAs) play a significant role in the cellular progression from a normal phenotype to a cancerous phenotype. Recently, many studies have shown that there are two essential regulatory ncRNAs, miRNAs (microRNAs) and lncRNAs, which are closely related to EMT. In this review, we conducted a comprehensive investigation of the dysregulated lncRNAs and miRNAs in gliomas with particular attention to the function and regulatory mechanisms of several important lncRNAs and miRNAs, and we discussed their roles as glioma diagnostic and prognostic biomarkers and their potential clinical applications as therapeutic targets.     

MiR-143-3p controls TGF-β1-induced cell proliferation and extracellular matrix production in airway smooth muscle via negative regulation of the nuclear factor of activated T cells 1

MicroRNAs (miRNAs) are small noncoding RNAs that function in diverse biological processes. However, little is known about the precise role of microRNAs in the functioning of airway smooth muscle cells (ASMCs). Here, we investigated the potential role and mechanisms of the miR-143 -3p on proliferation and the extracellular matrix (ECM) protein production of ASMCs. We demonstrated that miR-143-3p was aberrantly lower in ASMCs isolated from individuals with asthma than in individuals without asthma. Meanwhile, TGF-β1 caused a marked decrease in a time-dependent manner in miR-143-3p expression in ASMCs from asthmatics. Additionally, the overexpression of miR- 143-3p robustly reduced TGF-β1-induced ASMCs proliferation and downregulated CDK and cyclin expression, whereas the inhibition of miR-143-3p significantly enhanced ASMCs proliferation and upregulated the level of CDKs and cyclins. Re-expression of miR-143-3p attenuated ECM protein deposition reflected as a marked decrease in the expression of type I collagen and fibronectin, whereas miR-143-3p downregulation caused an opposite effect on the expression of type I collagen and fibronectin. Moreover, qRT-PCR and western blot analysis indicated that miR-143-3p negatively regulated the expression of nuclear factor of activated T cells 1 (NFATc1). Subsequent analyses demonstrated that NFATc1 was a direct and functional target of miR-143-3p, which was validated by the dual luciferase reporter assay. Most importantly, the overexpression of NFATc1 effectively reversed the inhibition of miR-143-3p on TGF-β1-induced proliferation, and strikingly abrogated the effect of miR-143-3p on the expression of CDK4 and Cyclin D1. Together, miR-143-3p may function as an inhibitor of asthma airway remodeling by suppressing proliferation and ECM protein deposition in TGF-β1-mediated ASMCs via the negative regulation of NFATc1 signaling, suggesting miR-143-3p as a potential therapeutic target for asthma.