bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020‒07‒19
ten papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Cell Cycle. 2020 Jul 14. 1-9
    Wang Z, Chang X, Zhu G, Gao X, Chang L.
      Long non-coding RNA metastasis associated with lung adenocarcinoma transcript 1 (MALAT1) contributes to chemotherapy resistance in some cancers, but the role of MALAT1 in sunitinib (SU) chemoresistance of carcinoma (RCC) is still unknown. In this study, MALAT1 expression in SU-resistance tumor tissues and cells was tested by qRT-PCR. Then, CCK-8, Annexin V-FITC/PI, transwell, and Western blotting assays were used to evaluate cell viability and IC50, apoptosis, cell invasion, and resistance of SU-resistance RCC cells after transfected with small interfering RNA against MALAT1. Further, RNA pull-down and luciferase reporter assay were applied to investigate the underlying mechanism of MALAT1 in SU resistance. The results showed that MALAT1 expression was dramatically upregulated in SU-resistance RCC tissues and cell lines. Knockdown of MALAT1 inhibited proliferation, invasion, and SU chemoresistance, but induced apoptosis in RCC cells. The results of RNA pull-down and luciferase reporter assay indicated that MALAT1 could interact with miR-362-3p and miR-362-3p interact with RasGAP SH3-domain-Binding Protein 1 (G3BP1). Moreover, G3BP1 also played a role in SU chemoresistance of RCC cells, and MALAT1 could perform as a miR-362-3p sponge to modulate G3BP1 expression. Rescue experiments suggested that downregulation of miR-362-3p and overexpression of G3BP1 can reverse the SU chemosensitivity of MALAT1 knockdown in RCC cells. In conclusion, depletion of LncRNA MALAT1 inhibited SU chemoresistance through modulating G3BP1 via sponging miR-362-3p in RCC cells, suggesting that targeting MALAT1 may be a potential therapeutic strategy for SU-resistance RCC.
    Keywords:  G3BP1; MALAT1; MiR-362-3p; renal cell carcinoma; sunitinib resistance
  2. Front Physiol. 2020 ;11 622
    Liu X, Zhu N, Zhang B, Xu SB.
      Acute kidney injury (AKI) is a common and serious complication of sepsis accompanied by kidney dysfunction resulting from various etiologies and pathophysiological processes. Unfortunately, there is currently no ideal therapeutic strategy for AKI. Numerous studies have confirmed that long noncoding RNAs (lncRNAs) play important regulatory roles in the pathogenesis of sepsis-associated AKI. In this study, lncRNA TCONS_00016406 (termed lncRNA 6406), a novel lncRNA identified by using TargetScan, was significantly downregulated in the kidney tissues of mice with sepsis-associated AKI. This study aimed to explore the role of lncRNA 6406 in lipopolysaccharide (LPS)-induced AKI and its potential molecular mechanism. The models of sepsis-induced AKI (called LPS-induced AKI models) in mice and cell lines were established with male C57BL/6 mice and renal tubular epithelial (PTEC) cells, respectively. Twenty-four hours after LPS administration, kidneys and cell samples were collected after various treatments to examine the alterations in the lncRNA 6406 levels and to evaluate the effects on LPS-induced inflammation, oxidative stress, and apoptosis through real-time PCR (RT-PCR) analysis, western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The results revealed that lncRNA 6406 could significantly attenuate LPS-induced AKI, as shown by the alleviation of inflammation, the suppression of oxidative stress and the inhibition of apoptosis. Mechanistically, a luciferase reporter assay and additional research showed that lncRNA 6406 functioned as a ceRNA to sponge miRNA-687, thereby modulating LPS-stimulated AKI by targeting the miR-687/PTEN axis; thus, this study presents a novel therapeutic strategy or sepsis-associated AKI.
    Keywords:  PTEN; acute kidney injury; long noncoding RNA 6406; miR-687; sepsis
  3. Curr Genomics. 2020 Jan;21(1): 37-45
    Zhu Y, Yan Z, Tang Z, Li W.
      The pluripotent state of stem cells depends on the complicated network orchestrated by thousands of factors and genes. Long noncoding RNAs (lncRNAs) are a class of RNA longer than 200 nt without a protein-coding function. Single-cell sequencing studies have identified hundreds of lncRNAs with dynamic changes in somatic cell reprogramming. Accumulating evidence suggests that they participate in the initiation of reprogramming, maintenance of pluripotency, and developmental processes by cis and/or trans mechanisms. In particular, they may interact with proteins, RNAs, and chromatin modifier complexes to form an intricate pluripotency-associated network. In this review, we focus on recent progress in approaches to profiling functional lncRNAs in somatic cell reprogramming and cell differentiation.
    Keywords:  Pluripotency; RNA sequencing; epigenetics; long noncoding RNA; reprogramming; stem cells
  4. Eur Heart J. 2020 Jul 13. pii: ehaa519. [Epub ahead of print]
    Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T.
      AIMS: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.METHOD AND RESULTS: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.
    CONCLUSION: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.
    Keywords:  Cardiovascular disease; Gene therapy; Hypertrophy; Long non-coding RNA; Translational research
  5. Epigenomics. 2020 Jul 17.
    Guo G, Chen A, Ye L, Wang H, Chen Z, Yan K, Shi X, Li B, Lin Q, You X, Jiang C, Zhang Q, Ding X, Xue X, Zhang H.
      Aim: We aimed to identify differentially expressed Long noncoding RNAs (lncRNAs) and explore their functional roles in systemic lupus erythematosus (SLE). Materials & methods: We identified dysregulated lncRNAs and investigated their prognostic values and potential functions using MiRTarget2, catRAPID omics and Bedtools/blast/Pearson analyses. Results: Among the 143 differentially expressed lncRNAs, TCONS_00483150 could be used to distinguish patients with SLE from healthy controls and those with rheumatoid arthritis and patients with active/stable SLE from healthy controls. TCONS_00483150 was significantly correlated with anti-Rib-P antibody positivity and low C3 levels; TCONS_00483150 dysregulation might contribute to the metabolism of RNA and proteins in SLE patients. Conclusion: Overall, our findings offer a transcriptome-wide overview of aberrantly expressed lncRNAs in patients with SLE and highlight TCONS_00483150 as a potential novel diagnostic biomarker.
    Keywords:  RNA-sequencing; biomarker; long noncoding RNA; systemic lupus erythematosus
  6. Methods Mol Biol. 2020 ;2161 29-36
    Nishikawa M, Yanagawa N.
      Despite recent advance in our understanding on the role of long noncoding RNAs (lncRNAs), the function of the vast majority of lncRNAs remains poorly understood. To characterize the function of lncRNAs, knockdown studies are essential. However, the conventional silencing methods for mRNA, such as RNA interference (RNAi), may not be as efficient against lncRNAs, partly due to the mismatch of the localization of lncRNAs and RNAi machinery. To circumvent such limitation, a new technique has recently been developed, i.e., locked nucleic acid (LNA) gapmers. This system utilizes RNase H that distributes evenly in both nucleus and cytoplasm and is expected to knock down lncRNAs of interest more consistently regardless of their localization in the cell. In this chapter, we describe the procedure with tips to silence lncRNAs by LNA gapmers, by using mouse nephron progenitor cells as an example.
    Keywords:  Gapmer; Gymnosis; Knockdown; Nephron progenitor cells; lncRNA; ncRNA
  7. FEBS Open Bio. 2020 Jul 12.
    Xie J, Zhong Y, Rong C, Li G, Luo Y, Yang J, Sun Z, Liu Y, Liu P, Wang N, An J, Li C, Song Y.
      The identification of non-invasive biomarkers for detection of renal cell carcinoma (RCC) in early-stage patients may help improve disease outcome. Certain long noncoding RNAs (lncRNAs) have been reported to be possible biomarkers for diagnosis and prognosis of cancer. Here, we examined the suitability of the lncRNA LINC00887 as a potential biomarker for RCC, as its expression has been shown to be elevated in RCC tissue versus normal tissue in the Gene Expression Profiling Interactive Analysis (GEPIA) database. We found that LINC00887 expression is significantly increased in early-stage RCC tissues and serum of early-stage RCC patients compared with matched normal tissues and serum of healthy subjects, respectively. We also demonstrated that elevated serum LINC00887 is generated from the tumor tissues of RCC patients. Moreover, a receiver operating characteristic (ROC) curve was generated to analyze the diagnostic value of serum LINC00887. An area under the ROC cure differentiating early-stage RCC patients from healthy subjects was 0.8001, with 71.05% sensitivity and 89.87% specificity. Furthermore, we found that LINC00887 promotes RCC cell proliferation in vitro. Together, our findings suggest that a serum LINC00887 signature is associated with RCC cell proliferation and may be a potential biomarker for detection of early-stage RCC.
    Keywords:  LINC00887; biomarker; cell proliferation; renal cell carcinoma
  8. J Bioenerg Biomembr. 2020 Jul 14.
    Tan J, Fan J, He J, Zhao L, Tang H.
      Sepsis-induced acute kidney injury (AKI) represents a severe medical complication. Recently, there is growing evidence indicating the regulatory role of long non-coding RNAs (lncRNAs) in AKI pathophysiology. The present study investigated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) expression in septic AKI patients and to decipher the relevant mechanisms underlying DLX6-AS1-mediated HK-2 cell pyroptosis in lipopolysaccharide (LPS)-induced AKI. The results revealed that DLX6-AS1 was up-regulated in the serum from septic AKI patients. DLX6-AS1 expression were positively associated with the creatinine levels in the serum from the septic AKI patients. In vitro studies showed that LPS induced cytotoxicity and enhanced DLX6-AS1 expression of HK-2 cells; increased NLR family pyrin domain containing 3 (NLRP3), interleukin (IL)-1β and IL-18 expression. DLX6-AS1 overexpression promoted cytotoxicity and pyroptosis of HK-2 cells; while DLX6-AS1 knockdown counteracted the LPS-induced cytotoxicity and pyroptosis of HK-2 cells. More importantly, DLX6-AS1 sponged miR-223-3p resulting in repression of miR-223-3p expression in HK-2 cells. MiR-223-3p could bind to the 3' untranslated region of NLRP3, which results in the suppressed NLRP3 expression of HK-2 cells. Further rescue experiments showed that enhanced miR-223-3p expression partially reversed the cytotoxicity and pyroptosis of HK-2 cells upon LPS stimulation or with DLX6-AS1 overexpression. Conclusively, this study identified enhanced DLX6-AS1 expression in the serum from AKI patients. Further mechanistic findings deciphered that DLX6-AS1 mediated LPS-mediated cytotoxicity and pyroptosis in HK-2 via miR-223-3p/NLRP3 axis.
    Keywords:  DLX6-AS1; Lipopolysaccharide; NLRP3; Pyroptosis; Sepsis-induced AKI; miR-223-3p
  9. Cell Death Discov. 2020 ;6 55
    Lin M, Wang ZW, Zhu X.
      FBXO protein 45 (FBXO45), a substrate-recognition subunit of E3 ligases, has been characterised to have pivotal roles in many human diseases, including nervous system diseases, inflammatory diseases and human malignancies. In this article, we describe the expression of FBXO45 in several types of human tumour specimens and highlight the downstream substrates of FBXO45. Moreover, the biological functions of FBXO45 in the regulation of proliferation, apoptosis, the cell cycle and metastasis are mentioned. Furthermore, we describe that the expression level of FBXO45 is regulated by several upstream factors such as miR-27a, Hey1, m6A and the lncRNA RP11. As FBXO45 has a critical role in tumorigenesis and progression, FBXO45 might be a novel therapeutic target for cancer treatment.
    Keywords:  Oncogenes; Targeted therapies
  10. Front Genet. 2020 ;11 501
    Ryu J, Lee C.
      Ribosomal proteins (RPs) are essential components that translate genetic information from mRNA templates into proteins. Their expressional dysregulation adversely affects the survival and growth of human cells. Nevertheless, little is known about the nucleotide sequences regulating the expression of RPs. Genome-wide associations for expression level of 70 RP genes were conducted across expression stages. Eighteen expression regulatory quantitative trait loci (erQTLs) were identified for protein abundances of 21 RPs (P < 1 × 10-5), but not for their mRNA expression and ribosome occupancy (P > 1 × 10-5). These erQTLs for protein abundance (pQTLs) were all trans-acting. Three of the pQTLs were associated with the expression of long noncoding RNAs (lncRNAs). Target genes of these lncRNAs may produce ribosomal components or may control the metabolic cues for ribosome synthesis. mRNAs of the RP genes extensively interact with miRNAs. The protein-specific erQTLs may become engendered by intensive miRNA controls at the translational stage, which in turn can produce RPs efficient in handling instantaneous cell requirements. This study suggests that the expression levels of RPs may be greatly influenced by trans-acting regulation, presumably via interference of miRNAs and target genes of lncRNAs. Further studies are warranted to examine the molecular functions of pQTLs presented in this study and to understand the underlying regulatory mechanisms of gene expression of RPs.
    Keywords:  expression regulatory quantitative trait loci; lncRNA; pQTL; ribosomal protein; trans-acting regulation