miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

Nat Commun. 2018 Nov 30;9(1):5110. doi: 10.1038/s41467-018-07561-8.

Abstract

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Endoplasmic Reticulum-Associated Degradation / genetics
  • Endoplasmic Reticulum-Associated Degradation / physiology*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • In Situ Hybridization
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • MicroRNAs / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / physiology
  • Xenograft Model Antitumor Assays

Substances

  • Activating Transcription Factor 6
  • Membrane Proteins
  • MicroRNAs
  • TUSC3 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Endoribonucleases