bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020‒06‒28
seven papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Int J Genomics. 2020 ;2020 4301634
    Liu Z, Wang Z, Wang X, Lu M, Chen G.
      Several studies have indicated that HOXA transcript at the distal tip (HOTTIP) play important roles in the tumorigenesis and development of various cancers. We aim to investigate the expression and prognostic value of HOTTIP in clear cell renal cell carcinoma (ccRCC). A systematic review of PubMed, Embase, Medline, and Web of Science databases was performed to select eligible literatures relevant to the correlation between HOTTIP expression and clinical outcome of different cancers. The association between the HOTTIP level and overall survival (OS), lymph node metastasis (LNM), or clinical stage was subsequently analyzed. Survival analyses were performed in a large cohort of more than 500 patients with ccRCC from The Cancer Genome Atlas (TCGA) using bioinformatic methods. Seventeen studies with a total of 1594 patients with thirteen kinds of carcinomas were included in this analysis. The result showed that high HOTTIP expression could predict worse outcome in cancer patients, with the pooled hazard ratio (HR) of 2.34 (95% confidence interval (CI) 1.96-2.79, p < 0.0001). The result also showed that elevated HOTTIP expression was correlated with more LNM (OR = 2.61, 95% CI 1.91-3.58, p < 0.0001) and advanced clinical stage (OR = 3.57, 95% CI 2.58-4.93, p < 0.0001). We further validated that ccRCC patients with higher HOTTIP expression tend to have unsatisfactory outcomes both in the entire TCGA dataset and different clinical stratums, like age, grade, and stage. The tumor of those patients was associated with a larger size, easier to metastasis, advanced clinical stage, and a higher pathological grade. These findings suggested that increased HOTTIP expression might act as a novel prognostic marker for ccRCC patients.
  2. J Cell Physiol. 2020 Jun 24.
    Jiang Y, Zhang H, Li W, Yan Y, Yao X, Gu W.
      Increasing evidence suggests that long noncoding RNAs (lncRNAs) are pivotal regulators in oncogenesis. However, the role of numerous lncRNAs has never been unmasked in clear cell renal cell carcinoma (ccRCC). Presently, we investigated the function of long intergenic nonprotein coding RNA 1426 (LINC01426) in ccRCC, as The Cancer Genome Atlas data indicated that LINC01426 was highly expressed in ccRCC tissues and its overexpression was correlated with disappointing prognosis. First, we verified that LINC01426 was indeed upregulated in ccRCC cell lines and its depletion restrained ccRCC cell proliferation and migration. Besides, we proved that LINC01426 facilitated ccRCC tumorigenesis via forkhead box M1 (FOXM1). Moreover, it was revealed that miR-423-5p was downregulated and directly targeted FOXM1 in ccRCC, and that LINC01426 positively regulated FOXM1 via its inhibition on miR-423-5p. Notably, we also uncovered that miR-423-5p was transcriptionally silenced by CTBP1 and HDAC2. Of importance, LINC01426 was certified to distribute both in the cytoplasm and the nucleus of ccRCC cells, and it increased CTBP1 expression through recruiting insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) in cytoplasm whereas interacted with CTBP1 protein to improve the transcriptional repression on miR-423-5p in nucleus. Jointly, our observations unveiled that LINC01426 aggravates ccRCC progression via IGF2BP1/CTBP1/HDAC2/miR-423-5p/FOXM1 axis, highlighting LINC01426 as a novel promising target for ccRCC treatment.
    Keywords:  CTBP1; FOXM1; IGF2BP1; LINC01426; ccRCC; miR-423-5p
  3. Front Pharmacol. 2020 ;11 808
    Jin Y, Liu J, Liu Y, Liu Y, Guo G, Yu S, An R.
      Aims: Oxymatrine (OMT) has been identified to possess immunomodulatory, antiinflammatory and anticancer properties. This study aimed to investigate its precise function and the underlying molecular mechanisms in renal cell carcinoma progression.Methods: The antineoplastic effect of oxymatrine was investigated by CCK-8 assay, cell cycle analysis, apoptosis assay, wound healing experiment, transwell assay, and drug-sensitivity analysis in renal cancer cells following oxymatrine treatment. The modulation of oxymatrine on β-catenin was analyzed through western blot and immunofluorescence assay. β-catenin overexpression was employed to determine the key role of β-catenin in oxymatrine-inhibited renal cell carcinoma in vitro. In addition, animal model was established to investigate the effect of oxymatrine on tumor growth in vivo.
    Results: Oxymatrine inhibited renal cell carcinoma progression in vitro, including cell proliferation, apoptosis, migration, invasion and chemotherapy sensitivity. Further mechanistic studies demonstrated that oxymatrine exerted its antineoplastic effect through suppressing the expression of β-catenin. Moreover, in nude mice model, oxymatrine exhibited remarkable inhibition of tumor growth, which was consistent with our in vitro results.
    Conclusions: Our findings illuminate oxymatrine as an effective antitumor agent in renal cell carcinoma, and suggest it a promising therapeutic application in renal cell carcinoma treatment.
    Keywords:  apoptosis; chemotherapy sensitivity; invasion; migration; oxymatrine; proliferation; renal cell carcinoma; β-catenin
  4. Biomolecules. 2020 Jun 22. pii: E937. [Epub ahead of print]10(6):
    Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S.
      Systemic lupus erythematosus (SLE) is a chronic immune-related disorder designated by a lack of tolerance to self-antigens and the over-secretion of autoantibodies against several cellular compartments. Although the exact pathophysiology of SLE has not been clarified yet, this disorder has a strong genetic component based on the results of familial aggregation and twin studies. Variation in the expression of non-coding RNAs has been shown to influence both susceptibility to SLE and the clinical course of this disorder. Several long non-coding RNAs (lncRNAs) such as GAS5, MALAT1 and NEAT1 are dysregulated in SLE patients. Moreover, genetic variants within lncRNAs such as SLEAR and linc00513 have been associated with risk of this disorder. The dysregulation of a number of lncRNAs in the peripheral blood of SLE patients has potentiated them as biomarkers for diagnosis, disease activity and therapeutic response. MicroRNAs (miRNAs) have also been shown to affect apoptosis and the function of immune cells. Taken together, there is a compelling rationale for the better understanding of the involvement of these two classes of non-coding RNAs in the pathogenesis of SLE. Clarification of the function of these transcripts has the potential to elucidate the molecular pathophysiology of SLE and provide new opportunities for the development of targeted therapies for this disorder.
    Keywords:  lncRNA; miRNA; systemic lupus erythematosus
  5. Annu Rev Biochem. 2020 Jun 20. 89 283-308
    Rinn JL, Chang HY.
      We have known for decades that long noncoding RNAs (lncRNAs) can play essential functions across most forms of life. The maintenance of chromosome length requires an lncRNA (e.g., hTERC) and two lncRNAs in the ribosome that are required for protein synthesis. Thus, lncRNAs can represent powerful RNA machines. More recently, it has become clear that mammalian genomes encode thousands more lncRNAs. Thus, we raise the question: Which, if any, of these lncRNAs could also represent RNA-based machines? Here we synthesize studies that are beginning to address this question by investigating fundamental properties of lncRNA genes, revealing new insights into the RNA structure-function relationship, determining cis- and trans-acting lncRNAs in vivo, and generating new developments in high-throughput screening used to identify functional lncRNAs. Overall, these findings provide a context toward understanding the molecular grammar underlying lncRNA biology.
    Keywords:  MPRNA; RNA grammar; RNA in vivo; RNA structure; RNA–protein interactions; lncRNA; long noncoding RNA; massively parallel RNA reporter gene assays; nuclear localization
  6. Int J Cancer. 2020 Jun 23.
    Wu Y, Yang Y, Gu H, Tao B, Zhang E, Wei J, Wang Z, Liu A, Sun R, Chen M, Fan Y, Mao R.
      Enhancer can transcribe RNAs, however, most of them were neglected in traditional RNA-seq analysis workflow. Here, we developed a Pipeline for Enhancer Transcription (PET, for quantifying enhancer RNAs (eRNAs) from RNA-seq. By applying this pipeline on lung cancer samples and cell lines, we show that the transcribed enhancers are enriched with histone marks and transcription factor motifs (JUNB, Hand1-Tcf3, and GATA4). By training a machine learning model, we demonstrate that enhancers can predict prognosis better than their nearby genes. Integrating the Hi-C, ChIP-seq, and RNA-seq data, we observe that transcribed enhancers associate with cancer hallmarks or oncogenes, among which LcsMYC-1 (Lung cancer-specific MYC eRNA-1) potentially supports MYC expression. Surprisingly, a significant proportion of transcribed enhancers contain small protein-coding open reading frames (sORFs) and can be translated into microproteins. Our study provides a computational method for eRNA quantification and deepens our understandings of the DNA, RNA, and protein nature of enhancers. This article is protected by copyright. All rights reserved.
    Keywords:  Enhancer RNA; eRNA pipeline; sORF; transcription factor
  7. J Exp Clin Cancer Res. 2020 Jun 20. 39(1): 117
    Grillone K, Riillo C, Scionti F, Rocca R, Tradigo G, Guzzi PH, Alcaro S, Di Martino MT, Tagliaferri P, Tassone P.
      The discovery of the role of non-coding RNAs (ncRNAs) in the onset and progression of malignancies is a promising frontier of cancer genetics. It is clear that ncRNAs are candidates for therapeutic intervention, since they may act as biomarkers or key regulators of cancer gene network. Recently, profiling and sequencing of ncRNAs disclosed deep deregulation in human cancers mostly due to aberrant mechanisms of ncRNAs biogenesis, such as amplification, deletion, abnormal epigenetic or transcriptional regulation. Although dysregulated ncRNAs may promote hallmarks of cancer as oncogenes or antagonize them as tumor suppressors, the mechanisms behind these events remain to be clarified. The development of new bioinformatic tools as well as novel molecular technologies is a challenging opportunity to disclose the role of the "dark matter" of the genome. In this review, we focus on currently available platforms, computational analyses and experimental strategies to investigate ncRNAs in cancer. We highlight the differences among experimental approaches aimed to dissect miRNAs and lncRNAs, which are the most studied ncRNAs. These two classes indeed need different investigation taking into account their intrinsic characteristics, such as length, structures and also the interacting molecules. Finally, we discuss the relevance of ncRNAs in clinical practice by considering promises and challenges behind the bench to bedside translation.
    Keywords:  Cancer genetics; Long-non coding RNAs; Non-coding RNAs; lncRNAs; miRNAs; microRNAs; ncRNA functions