A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway

Int J Biol Sci. 2022 Jul 18;18(13):4853-4868. doi: 10.7150/ijbs.72838. eCollection 2022.


During tumor progression, tumor cells are exposed to various stress conditions, which result in endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) to restore ER homeostasis. Accumulating evidence reported the orchestrating role of ER stress in epithelial-mesenchymal transition (EMT) progress, but the detailed mechanism was unclear. Here, we identified ectopic expression of TMTC3 in cells undergoing ER stress and verified the association with EMT markers through the cellular model of ER stress and database analysis. TMTC3 was abnormally highly expressed in squamous cell carcinomas (SCCs), and regulated by TP63, an SCCs-specific transcription factor. Biological function experiments indicated that TMTC3 promoted a malignant phenotype in vitro, and accelerated tumor growth and metastasis in vivo. RNA-seq analyses and further experiments revealed that TMTC3 promoted the expression of EMT markers via interleukin-like EMT inducer (ILEI, FAM3C). Further studies on the mechanism showed that TMTC3 disrupted the interaction between PERK and GRP78 to activate the PERK pathway and promote the nuclear translocation of ATF4, which increased the transcriptional activity of ILEI. These findings indicated that TMTC3 activates GRP78/PERK signaling pathway during ER stress-induced EMT, which might serve as a potential therapeutic target in SCCs.

Keywords: EMT; ER stress; TMTC3; squamous cell carcinoma.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Carcinoma, Squamous Cell* / genetics
  • Carrier Proteins* / genetics
  • Carrier Proteins* / metabolism
  • Endoplasmic Reticulum Chaperone BiP* / metabolism
  • Endoplasmic Reticulum Stress
  • Humans
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Signal Transduction
  • eIF-2 Kinase* / metabolism


  • Carrier Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Membrane Proteins
  • TMTC3 protein, human
  • Activating Transcription Factor 4
  • EIF2AK3 protein, human
  • eIF-2 Kinase