USP47调控结直肠癌干性研究及新型抑制剂发现

	USP47调控结直肠癌干性研究及新型抑制剂发现; USP47 maintains the stemness of colorectal cancer cells and is inhibited by Parthenolide
	张少华
导师	李艳
摘要	Cancer stem cells (CSCs) are implicated in tumor initiation, invasion, recurrence and treatment resistance, so elucidation of the mechanisms underlying the cancer stem cells induction and development of drugs targeting CSCs is vital for cancer treatment. Growing evidence shows that the ubiquitin proteasome system plays an important role in the regulation of CSCs, and dysregulated deubiquitinase expression is closely related to the maintenance of the stemness of cancer stem cells. However, few studies on the DUBs involved in the modulation of colorectal cancer stem cells were reported. Our previous investigation found that the deubiquitinatinase USP47 may be an oncogene that promotes the occurrence and development of tumors, so we have conducted in-depth research on the role of USP47 in colorectal cancer. This thesis firstly analyzed the bioinformatics data on the expression of USP47 and the occurrence and development of colorectal cancers, and found that the expression of USP47 was up-regulated in the tissues of patients with colorectal tumors, and was closely related to the poor prognosis of the patients. Using shRNA-mediated knockdown of USP47 inhibited the proliferation and metastasis of colorectal tumor cell lines, and also inhibited the EMT phenotype. These results suggest that the excessive activation of USP47 is closely related to the occurrence, development and metastasis of colorectal tumors. We further discussed the relationship between USP47 and the stemness of colorectal tumors. Colorectal cancer stem cells were enriched by the mammosphere culture system, and it was found that USP47 was abnormally highly expressed in colorectal cancer stem cells, suggesting that USP47 is related to the stemness of colorectal cancer. In-depth research found that the knockout of USP47 significantly inhibited the formation of mammospheres. And USP47 knockdown reduced the ratio of CD133+ and CD44+/CD166+ colorectal cancer stem cells, and reduced the protein levels of colorectal cancer stem cell markers. These data indicate that USP47 is involved in the regulation and maintenance of stem cell-like characteristics of colorectal cancer cells. Next, we conducted the discovery of a new USP47 inhibitor. Through in vitro enzyme activity experiment and CETSA binding experiment, we found that PTL is an inhibitor of USP47. We tested the effect of PTL on colorectal cancer stem cells. We found that PTL can significantly inhibit the formation and passage of mammospheres, and reduce the ratio of CD44+/CD166+ colorectal cancer stem cells. In addition, PTL can also promote the apoptosis of colorectal cancer stem cells. In summary, our research discovered for the first time the important regulatory role of USP47 in the occurrence, development and metastasis of colorectal cancer. USP47 is closely related to the maintenance of the stemness of colorectal cancers. And PTL, as an inhibitor of USP47, has tumor therapeutic potential for targeting colorectal cancer stem cells.
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74498
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	张少华. USP47调控结直肠癌干性研究及新型抑制剂发现, USP47 maintains the stemness of colorectal cancer cells and is inhibited by Parthenolide[D],2021.

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张少华-张少华-201828010642（3280KB）	学位论文		限制开放	CC BY-NC-SA	请求全文