福克斯M1
吉西他滨
基因敲除
癌症研究
下调和上调
上皮-间质转换
胰腺癌
细胞凋亡
化疗
泛素
癌症
小RNA
生物
化学
生物化学
基因
遗传学
作者
Jinfeng Zhu,Jiefeng Zhao,Chen Luo,Zhengming Zhu,X. Y. Peng,Xiaojian Zhu,Kang Lin,Fanqin Bu,Wenjun Zhang,Qing X. Li,Kai Wang,Zhigang Hu,Xin Yu,Leifeng Chen,Rongfa Yuan
标识
DOI:10.1038/s41419-022-04960-0
摘要
Pancreatic cancer (PC) is one of the deadliest malignant tumors, and its resistance to gemcitabine chemotherapy is the primary reason for poor prognosis in patients. Ubiquitin-like protein FAT10 has recently been reported to promote tumor chemotherapy resistance. In this study, the expression of FAT10 in PC was significantly higher than that in adjacent noncancerous tissues. Increased expression of FAT10 in PC was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of FAT10 inhibits the proliferation and epithelial-mesenchymal transition (EMT) of PC cells, promotes the apoptosis of PC cells, and enhances sensitivity to gemcitabine chemotherapy. In addition, upregulation of FAT10 increased the expression of FOXM1 protein. The effect of downregulating FAT10 was reversed by FOXM1 overexpression, and FOXM1 knockdown inhibited EMT driven by FAT10 overexpression. Mechanistically, FAT10 stabilized the expression of FOXM1 by competing with ubiquitin to bind FOXM1 and inhibiting the ubiquitination-mediated degradation of FOXM1. In conclusion, the FAT10-FOXM1 axis is a pivotal driver of PC proliferation and gemcitabine resistance, and the results provide novel insights into chemotherapy resistance in PC.
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