| RRC ID |
83662
|
| Author |
Okano Y, Suzuki H, Watanabe Y, Abdelaziz M, Manevich L, Kawanishi K, Ozaki H, Ishii R, Matsumoto S, Goto N, Zheng L, Okita Y, Hwang J, Nakayama M, Shima Y, Sakamoto N, Noguchi M, Tabuchi K, Kato M.
|
| Title |
THG-1/TSC22D4 promotes interleukin-1 signaling through stabilization of TRAF6 in squamous cell carcinoma.
|
| Journal |
Mol Cancer Res
|
| Abstract |
Malignant neoplasms arise within a region of chronic inflammation caused by tissue injuries. Inflammation is a key factor involved in all aspects of tumorigenesis including initiation, proliferation, invasion, angiogenesis, and metastasis. Interleukin-1 (IL-1) plays critical functions in tumor development with influencing the tumor microenvironment and promoting cancer progression. However, the mechanism of continuous activation of IL-1-mediated inflammatory pathway in tumor has not been fully elucidated. This study provides a novel mechanism of the autocrine activation of IL-1 signaling in squamous cell carcinoma (SCC) through a novel oncoprotein, TSC-22 homologous gene-1 (THG-1, also known as TSD22D4). The RNA sequencing analysis revealed that THG-1 overexpression enhances the transcription of NF-κB targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through suppression of NF-κB nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TRAF6 through its E3 ubiquitin ligase activity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-κB activity in SCC cells. Public database analyses of head and neck SCC revealed that high expression of THG-1 is associated with activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of IL-1-mediated inflammatory pathway, which could contribute to the future diagnosis and immune therapy of SCCs. Implications: An oncoprotein THG-1/TSD22D4 activates the IL-1-mediated inflammatory pathway through suppression of TRAF6 degradation, which mediates the continuous inflammation in tumors.
|
| Published |
2025-1-27
|
| DOI |
10.1158/1541-7786.MCR-24-0120
|
| PII |
751282
|
| PMID |
39869046
|
| MeSH |
Animals
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / metabolism
Carcinoma, Squamous Cell* / pathology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Interleukin-1* / genetics
Interleukin-1* / metabolism
Intracellular Signaling Peptides and Proteins
Signal Transduction
Squamous Cell Carcinoma of Head and Neck* / genetics
Squamous Cell Carcinoma of Head and Neck* / metabolism
Squamous Cell Carcinoma of Head and Neck* / pathology
TNF Receptor-Associated Factor 6* / genetics
TNF Receptor-Associated Factor 6* / metabolism
|
| IF |
4.63
|
| Resource |
| Human and Animal Cells |
LK-2(RCB1970)
RERF-LC-AI(RCB0444)
EBC-1(RCB1965) |
