TUSC7 suppression of Notch activation through sponging MiR-146 recapitulated the asymmetric cell division in lung adenocarcinoma stem cells

Life Sci. 2019 Sep 1:232:116630. doi: 10.1016/j.lfs.2019.116630. Epub 2019 Jul 4.

Abstract

Aims: Lung adenocarcinoma consists of multiple therapeutic targets, however, patients will inevitably progress to later stage diagnosis with Tyrosine Kinase Inhibitor treatment resistance. We aim to investigate the roles of non-coding TUSC7 in ordering the cell division tendency, helping to sensitize the resistance in a miRNA incorporating way.

Materials and methods: Online study of bioinformatics analysis, molecular experiments of luciferase test, immunofluorescence staining and qRT-PCR were applied to dig out the mechanistic regulations.

Key findings: TUSC-7 inhibited the renewal ability of adenocarcinoma stem cells, yielding to asymmetric cell splitting. Informatics analysis and the luciferase testing confirmed the 3'UTR binding site, and revealed the post-transcriptional regulation of NUMB referring to miR-146. TUSC-7 sponged miR-146 and abolished its degradation toward to NUMB, and this integrated cascade made several genes become tangled to full functionality.

Significance: TUSC-7 was proved to be one strong suppressive lnc-RNA in lung adenocarcinoma stem cells, functioning through inactivating NOTCH signaling, and the turbulence on division modes precisely pointed to the key mechanisms of stem cells' renewal. The decreasing of tumor suppressive miR-146 was necessary in TUSC-7 conducted renewal repression, despite it alone could also reduce the renewal efficiency, indicating that more complicated non-coding genes may be involved in its regulation.

Keywords: Cell division mode; Lung adenocarcinoma stem cells; Notch signaling; Sponge regulation; TUSC7.

MeSH terms

  • 3' Untranslated Regions
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / metabolism*
  • Adenocarcinoma of Lung / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • RNA, Long Noncoding / physiology*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism

Substances

  • 3' Untranslated Regions
  • MIRN146 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Nerve Tissue Proteins
  • NUMB protein, human
  • RNA, Long Noncoding
  • Receptors, Notch
  • loc285194 LncRNA, human