CSE1L silence inhibits the growth and metastasis in gastric cancer by repressing GPNMB via positively regulating transcription factor MITF

J Cell Physiol. 2020 Mar;235(3):2071-2079. doi: 10.1002/jcp.29107. Epub 2019 Jul 25.

Abstract

Human chromosomal segregation 1-like (CSE1L) gene functions as a key molecular mediator in cellular proliferation, invasion, and apoptosis. The association of CSE1L with tumor progression has been reported in diverse human cancers. A greater understanding of CSE1L molecular mechanism is beneficial for cancer treatment. In the current study, we show that CSE1L was highly expressed in gastric cancer (GC) cell lines. CSE1L silence promoted apoptosis and inhibited cell proliferation and invasion. Overexpression of glycoprotein nonmetastatic melanoma protein B (GPNMB) reversed the anticancer effect of CSE1L inhibition. CSE1L inhibition decreased GPNMB by microphthalmia-associated transcription factor (MITF). Moreover, GPNMB regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. Taken together, our study revealed that CSE1L inhibition decreased MITF and suppressed GPNMB expression, thereby activating the PI3K/Akt/mTOR and MEK/ERK signaling pathway, ultimately inhibiting the tumor growth and metastasis in GC.

Keywords: gastric cancer; glycoprotein nonmetastatic melanoma protein B; human chromosomal segregation 1-like gene; metastasis.

MeSH terms

  • Apoptosis / physiology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • Cellular Apoptosis Susceptibility Protein / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • MAP Kinase Signaling System / physiology
  • Membrane Glycoproteins / metabolism*
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Metastasis / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Cellular Apoptosis Susceptibility Protein
  • GPNMB protein, human
  • MITF protein, human
  • Membrane Glycoproteins
  • Microphthalmia-Associated Transcription Factor
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases