TSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-κB signaling

• Published in: Nature communications Vol. 9; no. 1; pp. 1423 - 12
• Main Authors: Zhang, Baozhu, Zhang, Zhao, Li, Lei, Qin, Yan-Ru, Liu, Haibo, Jiang, Chen, Zeng, Ting-Ting, Li, Meng-Qing, Xie, Dan, Li, Yan, Guan, Xin-Yuan, Zhu, Ying-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-04-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/109; 13/51; 13/89; 14/19; 38/77; 38/90; 631/67/1504/1477; 631/80/84/2336; 64/60; 96/63; Aged; Animals; beta-Transducin Repeat-Containing Proteins - genetics; beta-Transducin Repeat-Containing Proteins - metabolism; Biomarkers; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Degradation; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Esophagus; Female; Gelatinase B; Gene expression; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Lymph nodes; Lymphatic Metastasis; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Metastases; Metastasis; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Monocyte chemoattractant protein 1; multidisciplinary; Neoplasm Grading; Neoplasm Staging; Neoplasm Transplantation; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - genetics; NF-KappaB Inhibitor alpha - metabolism; NF-κB protein; Nuclear transport; Proteasomes; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Squamous cell carcinoma; Tetraspanins - antagonists & inhibitors; Tetraspanins - genetics; Tetraspanins - metabolism; Therapeutic applications; Tissues; Transcription activation; Transducin; Translocation; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03716-9

Beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) is crucial for the degradation of IκBα. Our previous transcriptome sequencing analysis revealed that
tetraspanin 15
(
TSPAN15
) was significantly upregulated in clinical oesophageal squamous cell carcinoma (OSCC) tissues. Here, we show that high TSPAN15 expression in OSCC tissues is significantly associated with lymph node and distant metastasis, advanced clinical stage, and poor prognosis. Elevated
TSPAN15
expression is, in part, caused by the reduction of miR-339-5p. Functional studies demonstrate that
TSPAN15
promotes metastatic capabilities of OSCC cells. We further show that TSPAN15 specifically interacts with BTRC to promote the ubiquitination and proteasomal degradation of p-IκBα, and thereby triggers NF-κB nuclear translocation and subsequent activation of transcription of several metastasis-related genes, including ICAM1, VCAM1, uPA, MMP9, TNFα, and CCL2. Collectively, our findings indicate that TSPAN15 may serve as a new biomarker and/or provide a novel therapeutic target to OSCC patients.
BTRC can activate NF-κB signaling through the ubiquitination and degradation of IκB-α. Here the authors show that TSPAN15 promotes metastasis of oesophageal squamous cell cancer by enhancing BTRC induced degradation of IκB-α and subsequent activation of NF-κB.