ISG15 and ISGylation modulates cancer stem cell-like characteristics in promoting tumor growth of anaplastic thyroid carcinoma

作者：Tong Xu, Chaozhuang Zhu, Jinming Chen, Feifeng Song, Xinxin Ren, Shanshan Wang, Xiaofen Yi, Yiwen Zhang, Wanli Zhang, Qing Hu, Hui Qin, Yujia Liu, Song Zhang, Zhuo Tan, Zongfu Pan, Ping Huang, Minghua Ge · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02751-9 · 被引用次数：32 · 研究领域：Cancer Cells and Metastasis、interferon and immune responses、Nanoplatforms for cancer theranostics

BACKGROUND: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs. METHODS: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC. RESULTS: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal e...