STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR/MAPK signaling pathway

Neoplasia. 2021 Jun;23(6):607-623. doi: 10.1016/j.neo.2021.05.011. Epub 2021 Jun 5.

Abstract

Tumor metastasis is a leading cause of death in lung adenocarcinoma (LUAD) patients, but the molecular events that regulate metastasis have not been completely elucidated. STAMBP is a deubiquitinating enzyme of the Jab1/MPN metalloenzyme family that regulates the stability of substrates in cells by specifically removing ubiquitin molecules. We found that STAMBP expression was increased in the cytoplasm of tumor cells from LUAD patients. The STAMBP level was closely associated with tumor size, lymph node invasion and neoplasm disease stage. A high STAMBP level predicted poor overall survival and disease-free survival in LUAD patients. STAMBP overexpression promoted cell migration and invasion, whereas STAMBP knockdown attenuated these processes in LUAD cells after epidermal growth factor treatment. Mechanistically, increased STAMBP expression promoted the stabilization of Epidermal growth factor receptor (EGFR), whereas STAMBP knockdown induced the degradation of EGFR. STAMBP may deubiquitinate EGFR by localizing in early endosomes and increase EGFR membrane localization in LUAD cells. The overexpression of STAMBP triggered the activation of MAPK signaling after epidermal growth factor treatment. In contrast, this activation was attenuated in STAMBP knockdown cells. Small molecule inhibitors of EGFR and MAPK signaling pathway may block STAMBP-induced cell mobility and invasion as well as ERK activation in cells. Importantly, STAMBP knockdown suppressed LUAD tumor growth and metastasis by regulating the EGFR-mediated ERK activation in a xenograft mouse model. Our findings identified STAMBP as a novel potential target for LUAD therapy.

Keywords: EGFR; ERK; Lung adenocarcinoma; MAPK; Metastasis; STAMBP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism*
  • Adenocarcinoma of Lung / pathology
  • Adult
  • Aged
  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Disease Models, Animal
  • Endosomal Sorting Complexes Required for Transport / genetics*
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Endosomes / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • Signal Transduction* / drug effects
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination
  • Xenograft Model Antitumor Assays

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Protein Kinase Inhibitors
  • STAMBP protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Mitogen-Activated Protein Kinases
  • Ubiquitin Thiolesterase