Endoplasmic reticulum-localized ECM1b suppresses tumor growth and regulates MYC and MTORC1 through modulating MTORC2 activation in esophageal squamous cell carcinoma

Cancer Lett. 2019 Oct 1:461:56-64. doi: 10.1016/j.canlet.2019.07.005. Epub 2019 Jul 15.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with dismal 5-year survival. Extracellular matrix protein 1 (ECM1) was identified as one of the most downregulated genes by transcriptomic analysis of normal esophageal/ESCC paired tissue samples. ECM1 plays oncogenic roles in cancer development in various cancer types. However, little is known about its role in ESCC. In vivo and in vitro functional assays coupled with analyses on public datasets and detailed molecular and mechanistic analyses were used to study the gene. We demonstrate that as opposed to the previously identified oncogenic role of ECM1a, ECM1b is a novel tumor suppressor in ESCC. ECM1 is significantly downregulated in ESCC and several other squamous cell carcinomas. ECM1b encodes a cellular protein that suppresses MYC protein expression and MTORC1 signaling activity. MTORC2 inactivation leads to suppressed MYC expression and MTORC1 signaling. ECM1b localizes to the endoplasmic reticulum and suppresses MTORC2 activation by inhibiting MTORC2/ribosome association. By regulating MTORC2/MYC/MTORC1 signaling, ECM1b suppresses general protein translation and enhances chemosensitivity. We provide evidence establishing a novel role of ECM1 in cancer that suggests ECM1b as a biomarker for ESCC disease management.

Keywords: Esophageal cancer; Protein translation; Signal transduction.

MeSH terms

  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Cycle
  • Cell Movement
  • Cell Proliferation
  • Endoplasmic Reticulum / metabolism*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma / genetics
  • Esophageal Squamous Cell Carcinoma / metabolism
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Phosphorylation
  • Prognosis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • ECM1 protein, human
  • Extracellular Matrix Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2