title: Role of long non-coding RNA lincNMR in nucleotide metabolism in cancer
creator: Gandhi, Minakshi
subject: ddc-570
subject: 570 Life sciences
subject: ddc-610
subject: 610 Medical sciences Medicine
description: Whole transcriptome analysis of the human genome has revealed that the majority of the genome gives rise to non-protein-encoding or simply non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) ranging from 200 nt to >100 kb represent a large subgroup of ncRNAs. They have emerged as critical players for not only regulating various physiological and developmental processes but also various cancers including liver cancer. Global cancer statistics report of 2018 has shown liver cancer to be the fourth leading cause of cancer-related deaths worldwide and has predicted it to be the sixth most commonly diagnosed cancer. Notably, advanced stage liver cancer has a poor overall survival rate of less than 20 % - thus warranting further investigations into the understanding of molecular mechanisms driving hepatocarcinogenesis, contributing to the discovery of improved diagnostic, prognostic and  treatment modalities.  Here, I performed a transcriptome-wide profiling of lncRNAs in liver cancer and identified a novel lncRNA, which I named lincNMR (long intergenic non-coding RNA - Nucleotide Metabolism Regulator). LincNMR was induced six-fold in hepatocellular carcinoma compared to normal liver tissue. Depletion of lincNMR in multiple liver cancer cell lines invoked a strong proliferation defect and lead to an induction of senescence. This phenotype was also observed in multiple breast and lung cancer cell lines suggesting cancer-wide role of lincNMR. Silencing of lincNMR caused a strong depletion of the key dNTP synthesizing enzymes RRM2, TK1 and TYMS implicating lincNMR in regulation of nucleotide metabolism. Notably, dNTP levels were significantly decreased in liver cancer cells upon the loss of lincNMR. Importantly, the proliferation defect induced by downregulation of lincNMR could be rescued by bathing the cells in exogenous pools of extracellular dNTPs. An in vivo RNA Antisense Purification combined with mass spectrometry (RAP-MS) approach identified YBX1 as a direct interaction partner of lincNMR. Furthermore, I show YBX1 as a regulator of RRM2, TK1 and TYMS gene expression and found lincNMR to control the transactivational activity of YBX1 as measured in luciferase assays. Lastly, I established the relevance of lincNMR for tumor growth in vivo using the Chick Chorioallantoic Membrane (CAM) model. LincNMR-depleted tumors were significantly smaller in size and weight. In summary, I discovered a novel lncRNA, lincNMR, which regulates tumor cell proliferation through a YBX1-RRM2-TK1-TYMS axis governing nucleotide metabolism.
date: 2019
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/27053/1/PhD%20Thesis%20Minakshi%20Gandhi%20Final.pdf
identifier: DOI:10.11588/heidok.00027053
identifier: urn:nbn:de:bsz:16-heidok-270534
identifier:   Gandhi, Minakshi  (2019) Role of long non-coding RNA lincNMR in nucleotide metabolism in cancer.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/27053/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng