bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020‒08‒16
nine papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Cancer Sci. 2020 Aug 11.
    Liu Y, Li X, Zhang C, Zhang H, Huang Y.
      The pioneering work from Chen's lab identified Siglec-15 as novel tumor immune suppressor, while the regulatory mechanisms underlying the broad up-regulation of Siglec-15 in human cancers were obscure currently. Here we found long non-coding RNA (lncRNA) LINC00973 was higher in Siglec-15-positive clear-cell renal cell carcinoma (ccRCC), and LINC00973 positively regulated Siglec-15 expression at transcriptional level. This effect was evidently dependent on miR-7109-3p (designated as miR-7109 hereafter), and we provided evidences supporting that Siglec-15 as direct target of miR-7109. Via sponging miR-7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec-15, and consequently was involved in cancer immune suppression. We further demonstrated that LINC00973 and miR-7109 expression in ccRCC antagonistically influenced immune activation of co-cultured Jurkat cells. Our study highlighted the importance of LINC00973-miR-7109-Siglec-15 in immune evasion in ccRCC, which offered significant opportunity for both therapeutic intervention and diagnostic/prognostic exploitations.
    Keywords:  LINC00973; Siglec-15; clear-cell renal cell carcinoma; competing endogenous RNA; miR-7109-3p
  2. Cureus. 2020 Jul 05. 12(7): e9003
    Mihaylova G, Vasilev V, Kosturkova MB, Stoyanov GS, Radanova M.
      Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). LN often leads to kidney failure, affecting the quality of a patient's life. There are several classical biomarkers that assist nephrologists' daily practice. For more than 50 years, anti-double stranded DNA antibodies and complement components C3 and C4 have been used for LN disease activity evaluation. The major obstacle in the usage of conventional biomarkers is that none of them have both high specificity and high sensitivity. Moreover, an invasive kidney biopsy is still the gold standard for renal involvement detection in SLE patients. Therefore, new non-invasive biomarkers are needed for the early and accurate establishment of LN. Among the promising candidates are long non-coding RNAs (lncRNAs). Their dysregulation appears to have predictive and diagnostic potential. Furthermore, these biomarkers like other conventional biomarkers give insight into the pathogenesis of LN. This review aims to summarize the available information on lncRNAs in SLE patients and to present their future opportunities to add to the conventional biomarkers in the diagnosis and monitoring of LN.
    Keywords:  biomarkers; lncrna; lupus nephritis; systemic lupus erythematosus
  3. Am J Transl Res. 2020 ;12(7): 3884-3894
    Che J, Yao X, Wang C, Zheng J, Guo C.
      BACKGROUND: Hypoxia is common in solid tumor masses that has functional consequences for tumor progression. Previous studies demonstrated that nearly 80% renal cell carcinoma (RCC) are under hypoxia. However, effect and its mechanism of hypoxia on RCC cell invasion remains to be defined.METHODS: The shRNA expression vectors, which were constructed to express a short hairpin RNA against lncRNA and overexpression of lncRNA, were transfected into the RCC cell lines (SW839 and OSRC-2). Levels of lncRNA-ENST00000574654.1, VEGF-A and VEGF-C mRNA and protein were examined by real-time quantitative-fluorescent PCR and Western blot analysis, respectively. The effects of lncRNA silencing and overexpression on cell invasion of SW839 and OSRC-2 cells were evaluated with cell migration assay.
    RESULTS: Hypoxia significantly stimulated cell invasion in both RCC cell lines (SW839: 2.38 ± 0.19 of normoxia vs 7.83 ± 0.38 of hypoxia, P < 0.05; and OSRC-2: 1.00 ± 0.08 of normoxia vs 5.88 ± 0.32 of hypoxia, P < 0.05). LncRNA microarray analysis found that lncRNA-ENST00000574654.1 was down-regulated under hypoxia. Consistently, over-expression of lncRNA-ENST00000574654.1 resulted in significant blockade of hypoxia-induced RCC migration. Furthermore, expression of lncRNA-ENST00000574654.1 was regulated by HIF-1α and VEGA-A through interacting with hnRNP, which in turn regulated the RCC cell invasion.
    CONCLUSIONS: These findings suggested that hypoxia promoted RCC cell invasion through HIF-1α/lncRNA (ENST00000574654.1)/hnRNP/VEGF-A pathway. Targeting this pathway could potentially improve therapeutic outcomes of renal cell carcinoma.
    Keywords:  Renal cell carcinoma (RCC); hypoxia; invasion; long non-coding RNA (lncRNA); vascular endothelial growth factor (VEGF)
  4. Cell J. 2020 Jul;22(Suppl 1): 101-109
    Safarpour-Dehkordi M, Doosti A, Jami MS.
      Objective: Bacterial toxin can cause cell death through induction of apoptosis in cancer cell lines as well as changes in the expression patterns of long non-coding RNAs (lncRNAs) and genes. In the present study, the effect of tst gene on ACHN cell lines was reported along with proposing a novel pathway of apoptosis in kidney cancer.Materials and Methods: In this experimental study, effective lncRNAs and genes were predicted from different criteria for renal cell carcinoma (RCC) by bioinformatics methods and lncRNA-miRNA-mRNA interaction was constructed; then the effect of Staphylococcus aureus tst gene on induction of apoptosis pathways on ACHN and HDF cell lines was investigated.
    Results: After creation of lncRNA-miRNA-mRNA interaction, changes in expression levels of lncRNA LINC00847 (P=0.0024) and PTEN gene (P=0.0027) were identified, as potential apoptosis biomarkers for kidney cancer, after treating ACHN cell line by pCDNA3.1 (+)-tst compared to the empty vector. In contrast, there was no statistically significant difference in DICER1 expression levels in ACHN-tst cell (P≥0.05). In addition, transfection by pcDNA3.1 (+)-tst could increase ACHN cell apoptosis level (P<0.0001) compared to the pcDNA3.1 (+) group; but no significant effect was observed on normal cells.
    Conclusion: It is suggested that lncRNA LINC00847, discovered in this study, could provide a new landscape for researches aimed to determine relationship between functional lncRNA and RCC pathways. pcDNA3.1 (+)-tst was found to increase apoptosis in the transfected cells.
    Keywords:  Apoptosis; Long Non-Coding RNA; TSST-1 Toxin; mRNA; microRNA
  5. Arch Biochem Biophys. 2020 Aug 05. pii: S0003-9861(20)30539-7. [Epub ahead of print] 108530
    Chen H, Fan Y, Jing H, Tang S, Zhou J.
      Fibrosis is the final common pathological feature of a wide variety of chronic kidney disease (CKD). However, an understanding of the mechanisms underlying the development of renal fibrosis remains challenging and controversial. As the current focus of molecular research, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular noncoding RNAs (circRNAs), have powerful and abundant biological functions, which essentially makes them mediators of the physiological and pathological processes of various system diseases. The role of ncRNAs in renal fibrosis has also received great attention in recent years, but most research has mainly focused on miRNAs. In fact, although a large number of studies of lncRNAs have emerged recently, the role these molecules play in renal fibrosis haven't been fully understood till now. Thus, this review discusses the discovery of lncRNAs and their biological functions in different types of renal fibrosis, as well as the imminent applications of these findings in clinical use. Undoubtedly, in the future, further understanding of the function of all types of lncRNAs will reveal large breakthroughs in the treatment of renal fibrosis.
    Keywords:  Fibrosis; RNA; Renal; lncRNA
  6. Oncol Lett. 2020 Sep;20(3): 2420-2434
    Xu D, Dang W, Wang S, Hu B, Yin L, Guan B.
      Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of RCC; however, prognostic prediction tools for ccRCC are scant. Developing mRNA or long non-coding RNA (lncRNA)-based risk assessment tools may improve the prognosis in patients with ccRCC. RNA-sequencing and prognostic data from patients with ccRCC were downloaded from The Cancer Genome Atlas and the European Bioinformatics Institute Array database at the National Center for Biotechnology Information. Differentially expressed (DE) RNAs (DERs) and prognostic DERs were screened between less favorable and favorable prognoses using the limma package in R 3.4.1, and analyzed using univariate and multivariate Cox regression analyses, respectively. Risk score models were constructed using optimal combinations of DEmRNAs and DElncRNAs identified using the Least Absolute Shrinkage And Selection Operator Cox regression model of the penalized package. Associations between risk score models and overall survival time were evaluated. Independent prognostic clinical factors were screened using univariate and multivariate Cox regression analyses, and nomogram models were constructed. Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the clusterProfiler package in R3.4.1. A total of 451 DERs were identified, including 404 mRNAs and 47 lncRNAs, between less favorable and favorable prognoses, and 269 DERs, including 233 mRNAs and 36 lncRNAs, were identified as independent prognostic factors. Optimal combinations including 10 DEmRNAs or 10 DElncRNAs were screened using four risk score models based on the status or expression levels of the 10 DEmRNAs or 10 DElncRNAs. The model based on the expression levels of the 10 DEmRNAs had the highest prognostic power. These prognostic DEmRNAs may be involved in biological processes associated with the inflammatory response, complement and coagulation cascades and neuroactive ligand-receptor interaction pathways. The present validated risk assessment tool based on the expression levels of these 10 DEmRNAs may help to identify patients with ccRCC at a high risk of mortality. These 10 DEmRNAs in optimal combinations may serve as prognostic biomarkers and help to elucidate the pathogenesis of ccRCC.
    Keywords:  DEGs; lncRNAs; pathway enrichment analysis; prognostic model; risk score
  7. Cancers (Basel). 2020 Aug 07. pii: E2214. [Epub ahead of print]12(8):
    Outeiro-Pinho G, Barros-Silva D, Correia MP, Henrique R, Jerónimo C.
      Renal cell tumors (RCT) remain as one of the most common and lethal urological tumors worldwide. Discrimination between (1) benign and malignant disease, (2) indolent and aggressive tumors, and (3) patient responsiveness to a specific therapy is of major clinical importance, allowing for a more efficient patient management. Nonetheless, currently available tools provide limited information and novel strategies are needed. Over the years, a putative role of non-coding RNAs (ncRNAs) as disease biomarkers has gained relevance and is now one of the most prolific fields in biological sciences. Herein, we extensively sought the most significant reports on ncRNAs as potential RCTs' diagnostic, prognostic, predictive, and monitoring biomarkers. We could conclude that ncRNAs, either alone or in combination with currently used clinical and pathological parameters, might represent key elements to improve patient management, potentiating the implementation of precision medicine. Nevertheless, most ncRNA biomarkers require large-scale validation studies, prior to clinical implementation.
    Keywords:  Renal cell tumors; biomarkers; diagnosis; liquid biopsies; lncRNA; miRNA; non-coding RNAs; prognosis; renal cell carcinoma
  8. Oncol Lett. 2020 Oct;20(4): 53
    Zhang Y, Guan X, Wang H, Wang Y, Yue D, Chen R.
      Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is upregulated in numerous types of cancer, and is implicated in various cellular processes associated with cancer progression. However, the underlying molecular mechanisms by which MALAT1 regulates metastasis remain unclear. The present study investigated the expression of MALAT1 across a range of different cancer types by analyzing RNA sequencing data from The Cancer Genome Atlas database. The results indicate that the expression of MALAT1 is highly tissue-dependent and that MALAT1 is significantly overexpressed in renal clear cell carcinoma (KIRC). The biological role of MALAT1 in regulating KIRC cell migration was further investigated using molecular and cellular assays. The results demonstrate that MALAT1 regulates the expression of cofilin-1 (CFL1), potentially by regulating RNA splicing. MALAT1 knockdown decreased the expression of CFL1 at both the mRNA and protein levels, and affected cytoskeletal rearrangement by regulating the levels of F-actin via CFL1, leading to significantly decreased cellular migration. Clinical analysis confirmed a significant correlation between MALAT1 and CFL1 expression, implicating both genes as biomarkers for poor prognosis in KIRC. The present study demonstrates a novel mechanism by which MALAT1 regulates cell migration, which may be exploited to develop novel therapeutic strategies for managing renal cancer metastasis.
    Keywords:  CFL1; MALAT1; RCC; cell migration; cytoskeleton; lncRNA
  9. Exp Mol Pathol. 2020 Aug 10. pii: S0014-4800(20)30794-2. [Epub ahead of print] 104518
    Yu Y, Jiang H, Niu Y, Huang J, Zhang X, Liu X, Zhang Y, Liu S, Fu H, Yu C.
      BACKGROUND/AIMS: Long noncoding RNA (lncRNA) is a large and diverse class of RNA molecules, and has received widespread attention for its role in the regulation of various biological processes, including stem cell transformation, neurological disease, and tumorigenesis. However, the role of lncRNA in renal fibrosis remains unclear.METHODS: We investigated the expression of lncRNA-GAS5 by quantitative real-time polymerase chain reaction (PCR) or fluorescence in situ hybridization in chronic kidney disease (CKD) by designing both in vivo and in vitro experiments. With over-expression of GAS5 or knockdown GAS5, miR-21 and its downstream target genes were tested using quantitative real-time PCR or western blots. Mutants of miR-21 were designed and transfected in cells. GAS5 in the plasma and urine of patients with CKD was measured by quantitative real-time PCR.
    RESULTS: In normal rats, GAS5 was predominantly expressed in renal tubular epithelial cells. GAS5 induction was significantly reduced in obstructive kidneys at 7 days after unilateral ureteral obstruction. In vitro, GAS5 was inhibited in cultured normal rat renal proximal tubular cells (NRK-52E) after incubation with transforming growth factor β at 24 h. Ectopic over-expression of GAS5 repressed extracellular matrix (ECM) levels such as collagen type III and fibronectin 1. Conversely, knockdown GAS5 augmented ECM accumulation in NRK-52E cells. GAS5 suppressed miR-21 activity in a direct and mechanistic manner. It subsequently turned off the expression of miR-21 downstream target genes, matrix metallopeptidase 2 and 9, which resulted in excessive ECM synthesis and deposition. Of note, plasma GAS5 was positively correlated with estimated glomerular filtration rate levels in CKD patients with different etiologies while urine GAS5 was negatively correlated.
    CONCLUSION: Activation of lncRNA-GAS5 attenuates kidney fibrosis by modulating miR-21 activity and may serve as a surrogate biomarker in monitoring CKD progression.
    Keywords:  GAS5; Long noncoding RNA; Renal fibrosis; miR-21