FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.
FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.
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FAT10通过稳定FOXM1表达诱导上皮细胞向间充质细胞转化，从而促进胰腺癌的化疗耐药。
DOI：
10.1038/s41419-022-04960-0
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发表时间：
2022-05-25
影响因子：
9
通讯作者：
Yuan, Rongfa
中科院分区：
文献类型：
--
作者：
Zhu, Jinfeng;Zhao, Jiefeng;Luo, Chen;Zhu, Zhengming;Peng, Xingyu;Zhu, Xiaojian;Lin, Kang;Bu, Fanqin;Zhang, Wenjun;Li, Qing;Wang, Kai;Hu, Zhigang;Yu, Xin;Chen, Leifeng;Yuan, Rongfa
胰腺癌(PC)是死亡率最高的恶性肿瘤之一，其对吉西他滨化疗的耐药是导致患者预后不良的主要原因。泛素样蛋白FAT10最近被报道促进肿瘤化疗耐药。在本研究中，FAT10在PC组织中的表达显著高于癌旁组织。FAT10在PC中的高表达与晚期的TNM分期和总体生存率降低有关。功能实验表明，下调FAT10的表达抑制了PC细胞的增殖和上皮-间充质转化，促进了PC细胞的凋亡，增强了对吉西他滨化疗的敏感性。此外，上调FAT10还可增加FOXM1蛋白的表达。下调FAT10的作用可被FOXM1过表达逆转，FOXM1基因敲除可抑制FAT10过表达所驱动的EMT。在机制上，FAT10通过与泛素竞争结合FOXM1并抑制泛素化介导的FOXM1的降解来稳定FOXM1的表达。总之，FAT10-FOXM1轴是PC增殖和吉西他滨耐药的关键驱动因素，该结果为PC的化疗耐药提供了新的见解。
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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通讯作者：
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