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Войти в исследования Experimental cell research · 2026
BIRC3 Promotes BYSL Ubiquitination and Degradation and Attenuates WNT/β-Catenin Signaling and Malignant Phenotypes in Lung Squamous Cell Carcinoma.
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Ding Jianyi, Xu Yangjun, Feng Zhuyang, Liu Qiuxia, Zhang Jiandong, Wang Xiang, Luo Dongxu, Yu Guangmao, Wei Desheng, Zhu Ting
Аннотация
BACKGROUND: Lung squamous cell carcinoma (LUSC) is frequently characterized by aberrant activation of WNT/β-catenin signaling; however, the regulatory relationship between BIRC3 and BYSL in this pathway and in LUSC progression remains unclear. This study aimed to investigate the regulation of BYSL protein stability by BIRC3 and its association with malignant phenotypes in LUSC.
METHODS: The expression of BYSL and BIRC3 in LUSC was analyzed using The Cancer Genome Atlas (TCGA) database, and their protein expression levels were examined by Western blotting (WB) in five pairs of LUSC tumor tissues and matched adjacent non-tumor tissues. BYSL and BIRC3 were separately knocked down or overexpressed in NCI-H520 and NCI-H1703 cells, and cell proliferation, migration, and invasion were assessed using EdU, wound-healing, and Transwell assays. Co-immunoprecipitation, cycloheximide chase, MG132 treatment, and ubiquitination assays were performed to evaluate the interaction between BIRC3 and BYSL and the stability of BYSL protein. Cells were further subjected to combined shBYSL and oe-BIRC3 treatment or oe-BIRC3 plus the WNT/β-catenin pathway inhibitor MSAB, followed by analysis of pathway-related proteins and malignant cellular phenotypes. A nude mouse subcutaneous xenograft model was used for in vivo validation.
RESULTS: BYSL expression was elevated in LUSC tissues and cells, whereas BIRC3 expression was reduced in LUSC tissues. BYSL knockdown inhibited LUSC cell proliferation, migration, and invasion, whereas BYSL overexpression exerted opposite effects. BIRC3 interacted with BYSL; BIRC3 overexpression promoted BYSL ubiquitination and accelerated its proteasomal degradation, whereas BIRC3 knockdown reduced BYSL ubiquitination and enhanced BYSL protein stability. Both BIRC3 overexpression and BYSL knockdown were accompanied by decreased protein levels of WNT3A, β-catenin, TCF1, and c-Myc and attenuation of malignant cellular phenotypes, with more pronounced changes following combined intervention. In nude mice, BYSL knockdown inhibited xenograft tumor growth, and this inhibitory effect was further enhanced by combined BIRC3 overexpression.
CONCLUSION: BIRC3 interacts with BYSL and promotes its ubiquitination and proteasomal degradation. BIRC3 overexpression and BYSL knockdown are associated with attenuation of WNT/β-catenin signaling and suppression of malignant phenotypes in LUSC, supporting a regulatory relationship among BIRC3, BYSL, and WNT/β-catenin signaling.
METHODS: The expression of BYSL and BIRC3 in LUSC was analyzed using The Cancer Genome Atlas (TCGA) database, and their protein expression levels were examined by Western blotting (WB) in five pairs of LUSC tumor tissues and matched adjacent non-tumor tissues. BYSL and BIRC3 were separately knocked down or overexpressed in NCI-H520 and NCI-H1703 cells, and cell proliferation, migration, and invasion were assessed using EdU, wound-healing, and Transwell assays. Co-immunoprecipitation, cycloheximide chase, MG132 treatment, and ubiquitination assays were performed to evaluate the interaction between BIRC3 and BYSL and the stability of BYSL protein. Cells were further subjected to combined shBYSL and oe-BIRC3 treatment or oe-BIRC3 plus the WNT/β-catenin pathway inhibitor MSAB, followed by analysis of pathway-related proteins and malignant cellular phenotypes. A nude mouse subcutaneous xenograft model was used for in vivo validation.
RESULTS: BYSL expression was elevated in LUSC tissues and cells, whereas BIRC3 expression was reduced in LUSC tissues. BYSL knockdown inhibited LUSC cell proliferation, migration, and invasion, whereas BYSL overexpression exerted opposite effects. BIRC3 interacted with BYSL; BIRC3 overexpression promoted BYSL ubiquitination and accelerated its proteasomal degradation, whereas BIRC3 knockdown reduced BYSL ubiquitination and enhanced BYSL protein stability. Both BIRC3 overexpression and BYSL knockdown were accompanied by decreased protein levels of WNT3A, β-catenin, TCF1, and c-Myc and attenuation of malignant cellular phenotypes, with more pronounced changes following combined intervention. In nude mice, BYSL knockdown inhibited xenograft tumor growth, and this inhibitory effect was further enhanced by combined BIRC3 overexpression.
CONCLUSION: BIRC3 interacts with BYSL and promotes its ubiquitination and proteasomal degradation. BIRC3 overexpression and BYSL knockdown are associated with attenuation of WNT/β-catenin signaling and suppression of malignant phenotypes in LUSC, supporting a regulatory relationship among BIRC3, BYSL, and WNT/β-catenin signaling.