bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020‒09‒06
six papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Sci Rep. 2020 Sep 02. 10(1): 14412
      Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma (RCC). Despite the existing extensive research, the molecular and pathogenic mechanisms of ccRCC are elusive. We aimed to identify the immune-related lncRNA signature and molecular subtypes associated with ccRCC. By integrating 4 microarray datasets from Gene Expression Omnibus database, we identified 49 immune-related genes. The corresponding immune-related lncRNAs were further identified in the TCGA dataset. 12-lncRNAs prognostic and independent signature was identified through survival analysis and survival difference between risk groups was further identified based on the risk score. Besides, we identified 3 molecular subtypes and survival analysis result showed that cluster 2 has a better survival outcome. Further, ssGSEA enrichment analysis for the immune-associated gene sets revealed that cluster 1 corresponded to a high immune infiltration level. While cluster 2 and cluster 3 corresponded to low and medium immune infiltration level, respectively. In addition, we validated the 12-lncRNA prognostic signature and molecular subtypes in an external validation dataset from the ICGC database. In summary, we identified a 12-lncRNA prognostic signature which may provide new insights into the molecular mechanisms of ccRCC and the molecular subtypes provided a theoretical basis for personalized treatment by clinicians.
  2. Mol Ther Nucleic Acids. 2020 Aug 05. pii: S2162-2531(20)30232-8. [Epub ahead of print]22 1-16
      The transforming growth factor-β (TGF-β)/Smads signal plays an important role in cancer metastasis by mediating the epithelial-mesenchymal transition (EMT) in cancer cells. lnc-TSI is a recently identified long noncoding RNA that negatively regulates the TGF-β/Smads signal. The present study was conducted to test the hypothesis that lnc-TSI inhibits metastasis in clear cell renal cell carcinoma (ccRCC) by regulating the TGF-β/Smad3 pathway. Herein, we show that lnc-TSI was upregulated in ccRCC cells and tissue and was associated with activation of the TGF-β/Smads signal. Depleting lnc-TSI enhanced tumor cell invasion and metastasis in vitro and ccRCC lung metastasis in vivo, whereas overexpressing lnc-TSI inhibited ccRCC cell invasion and tumor metastasis. Mechanistic studies indicated that lnc-TSI specifically inhibited the phosphorylation of Smad3 and subsequent EMT by binding with the MH2 domain of Smad3 to block the interaction between Smad3 and TGF-β receptor I in ccRCC cells. In a cohort of 150 patients with ccRCC, expression of lnc-TSI in tumors was negatively correlated with phosphorylated (p)Smad3 and activated EMT markers. Patients with expression of tumor lnc-TSI greater than or equal to the median at radical nephrectomy had a higher survival rate compared to those with lnc-TSI below the median during follow-up. These findings reveal a new regulatory mechanism of ccRCC metastasis and suggest a potential molecular target for the development of anti-cancer drugs.
    Keywords:  TGF-β signaling; clear cell renal cell carcinoma; long noncoding RNA; metastasis
  3. Physiol Genomics. 2020 Aug 31.
      Long noncoding RNAs (lncRNAs) are intracellular transcripts longer than 200 nucleotides and lack the capacity to encode protein. A subclass of lncRNA known as long intergenic noncoding RNAs (lincRNAs) are transcribed from genomic regions that share no overlap with annotated protein-coding genes. Increasing evidence has shown that some annotated lincRNA transcripts do in fact contain open reading frames (ORFs) encoding functional short peptides in the cell. Few robust methods for lincRNA-encoded peptide identification have been reported, and the tissue-specific expression of these peptides has been largely unexplored. Here we propose an integrative workflow for lincRNA-encoded peptide discovery and tested it on the mouse kidney inner medulla (IM). In brief, low molecular weight protein fractions were enriched from homogenate of IM and trypsinized into shorter peptides, which were characterized using high resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). The challenge is to curate a hypothetical lincRNA-encoded peptide database for peptide-spectrum matching following LC-MS/MS. We performed RNA-Seq on IM, computationally filtered out reads overlapping with annotated protein-coding genes, and re-mapped the remaining reads to a database of mouse noncoding transcripts. The mapped transcripts are likely to be lincRNAs, and further searched for ORFs using an existing rule-based algorithm for peptide-spectrum matching. Peptides identified by LC-MS/MS were further evaluated using several quality control criteria and bioinformatics methods. We discovered three novel lincRNA-peptides, which are conserved in mouse, rat, and human. The workflow can be adapted for discovery of small protein-coding genes in any species or tissue where noncoding transcriptome information is available.
    Keywords:  RNA-Seq; lincRNA; noncoding RNA; protein mass spectrometry; proteogenomics
  4. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2020 Apr 28. pii: 1672-7347(2020)04-0435-05. [Epub ahead of print]45(4): 435-439
      Urinary calculi are characterized by high incidence and recurrence rate, which is a challenge in urology. The theory of Randall plaque is widely recognized by scholars. The mechanism of Randall plaque formation includes vascular calcification, osteogenic transformation and so on. However, it still lacks a unified theory for the Randall plaque formation. As an important type of non-coding RNA, long non-coding RNA (lncRNA) is closely related to the occurrence and progress of many diseases. The difference in lncRNA expression between the renal papillary tissues of non-calculous patients and the renal papillary tissues of Randall plaque in renal calculous patients suggests that lncRNA may be involved in the formation of Randall plaque. Pseudoxanthoma elasticum is a rare autosomal recessive hereditary disease, caused by a mutation in the ABCC6 gene. Patients with pseudoxanthoma elasticum have a high prevalence of calculi, and plaque formation is observed in the patient's kidney, which may suggest that mutation in the ABCC6 gene might be involved in the formation of Randall plaque.
    Keywords:  ABCC6; Randall plaque; kidney stones; long non-coding RNA
  5. J Cell Mol Med. 2020 Sep 05.
      Long non-coding RNAs (lncRNAs) have come out as critical molecular regulators of human tumorigenesis. In this study, we sought to identify and functionally characterize lncRNAs as potential mediators of colorectal cancer progression. We screened and identified a novel lncRNA, ADAMTS9-AS1, which was significantly decreased in colorectal cancer tissues and was correlated with clinical outcome of patients according to The Cancer Genome Atlas (TCGA) database. In addition, ADAMTS9-AS1 regulated cell proliferation and migration both in vitro and in vivo. Bioinformatics analysis revealed that overexpression of lncRNA-ADAMTS9-AS1 preferentially affected genes that were linked to proliferation and migration. Mechanistically, we found that ADAMTS9-AS1 obviously suppressed β-catenin, suggesting that Wnt signalling pathway participates in ADAMTS9-AS1-mediated gene transcriptional regulation in the suppression of colorectal tumorigenesis. Finally, we found that exosomal ADAMTS9-AS1 could serve as a diagnostic biomarker for colorectal cancer with AUC = 0.835 and 95% confidence interval = 0.777-0.911. Our data demonstrated that ADAMTS9-AS1 might play important roles in colorectal cancer by suppressing oncogenesis. Targeting ADAMTS9-AS1 may have potential clinical applications in colorectal cancer prognosis and treatment as an ideal therapeutic target. Finally, exosomal lncRNA-ADAMTS9-AS1 is a promising, novel diagnostic biomarker for colorectal cancer.
    Keywords:  ADAMTS9-AS1; EMT; LncRNA; colorectal cancer; exosomes
  6. Biochem Biophys Res Commun. 2020 Aug 28. pii: S0006-291X(20)31670-3. [Epub ahead of print]
      BACKGROUND: This study aimed to investigate the involvement of lncRNA CTBP1-AS2 in the progression of diabetic nephropathy (DN) by affecting high glucose (HG)-induced human glomerular mesangial cells (HGMCs).METHODS: HGMCs were selected for the establishment of cell injury induced by HG. The expression of CTBP1-AS2, miR-155-5p and FOXO1 was detected by real-time PCR and western blotting. The target association between miR-155-5p and CTBP1-AS2 or FOXO1 was confirmed by dual-luciferase reporter assays. Cell proliferation and oxidative stress were revealed by CCK-8 colorimetry, and the measurement of reactive oxygen species (ROS) and the activities of antioxidant enzymes. Extracellular matrix (ECM) protein accumulation and the production of inflammatory cytokines were investigated by western blotting and ELISA.
    RESULTS: The expression of CTBP1-AS2 was downregulated, and miR-155-5p was highly expressed in peripheral blood of DN patients and HG-treated HGMCs. Further investigation revealed that CTBP1-AS2 overexpression inhibited proliferation, oxidative stress, ECM accumulation and inflammatory response in HG-induced HGMCs. Mechanical analysis revealed that CTBP1-AS2 regulated FOXO1 expression via sponging miR-155-5p. Rescue experiments demonstrated that miR-155-5p overexpression or FOXO1 inhibition reversed the effects of CTBP1-AS2 in HG-stimulated HGMCs.
    CONCLUSION: Taken together, this study revealed CTBP1-AS2 attenuated HG-induced HGMC proliferation, oxidative stress, ECM accumulation, and inflammation through miR-155-5p/FOXO1 signaling.
    Keywords:  CTBP1-AS2; Diabetic nephropathy; ECM accumulation; Inflammation; Oxidative stress