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FAT10 通过稳定 FOXM1 的表达诱导上皮-间充质转化促进胰腺癌的化疗耐药性。

FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.

机构信息

Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.

Department of Pathology, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.

出版信息

Cell Death Dis. 2022 May 25;13(5):497. doi: 10.1038/s41419-022-04960-0.

DOI:10.1038/s41419-022-04960-0
PMID:35614040
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9132907/
Abstract

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.

摘要

胰腺癌（PC）是最致命的恶性肿瘤之一，其对吉西他滨化疗的耐药性是患者预后不良的主要原因。最近有报道称，泛素样蛋白 FAT10 可促进肿瘤化疗耐药性。在本研究中，FAT10 在 PC 中的表达明显高于相邻的非癌组织。PC 中 FAT10 的高表达与较晚的 TNM 分期和总生存率降低有关。功能实验表明，下调 FAT10 的表达可抑制 PC 细胞的增殖和上皮-间充质转化（EMT），促进 PC 细胞凋亡，并增强对吉西他滨化疗的敏感性。此外，上调 FAT10 增加了 FOXM1 蛋白的表达。FOXM1 过表达逆转了下调 FAT10 的作用，而 FOXM1 敲低抑制了 FAT10 过表达驱动的 EMT。从机制上讲，FAT10 通过与泛素竞争结合 FOXM1 并抑制 FOXM1 的泛素化介导降解来稳定 FOXM1 的表达。总之，FAT10-FOXM1 轴是 PC 增殖和吉西他滨耐药性的关键驱动因素，研究结果为 PC 的化疗耐药性提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/aedd6ba0082f/41419_2022_4960_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/aedd6ba0082f/41419_2022_4960_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/9fa3d100e27f/41419_2022_4960_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/03f21198d33b/41419_2022_4960_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/13440866f64f/41419_2022_4960_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/da79832c5756/41419_2022_4960_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06ee/9132907/6b15d3c72ebf/41419_2022_4960_Fig7_HTML.jpg
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