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

Research Paper

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

Hongyu Yuan1†, Zitong Zhao1†, Zichan Guo1, Liying Ma1, Jing Han2, Yongmei Song1✉

1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
2. Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei 050000, China.
† These authors contributed equally to this work.

Citation:
Yuan H, Zhao Z, Guo Z, Ma L, Han J, Song Y. A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. Int J Biol Sci 2022; 18(13):4853-4868. doi:10.7150/ijbs.72838. https://www.ijbs.com/v18p4853.htm
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Abstract

Graphic abstract

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: TMTC3, squamous cell carcinoma, EMT, ER stress


Citation styles

APA
Yuan, H., Zhao, Z., Guo, Z., Ma, L., Han, J., Song, Y. (2022). A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. International Journal of Biological Sciences, 18(13), 4853-4868. https://doi.org/10.7150/ijbs.72838.

ACS
Yuan, H.; Zhao, Z.; Guo, Z.; Ma, L.; Han, J.; Song, Y. A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. Int. J. Biol. Sci. 2022, 18 (13), 4853-4868. DOI: 10.7150/ijbs.72838.

NLM
Yuan H, Zhao Z, Guo Z, Ma L, Han J, Song Y. A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. Int J Biol Sci 2022; 18(13):4853-4868. doi:10.7150/ijbs.72838. https://www.ijbs.com/v18p4853.htm

CSE
Yuan H, Zhao Z, Guo Z, Ma L, Han J, Song Y. 2022. A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. Int J Biol Sci. 18(13):4853-4868.

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