Wnt/β-catenin信号通路调控NK细胞介导的肿瘤免疫和Brevinin-1RL1抗肿瘤研究

	Wnt/β-catenin信号通路调控NK细胞介导的肿瘤免疫和Brevinin-1RL1抗肿瘤研究; Studies of Wnt/β-catenin signaling in NK cell -mediated tumor immunity and anti-tumor of Brevinin-1RL1
	居晓曼
导师	李艳
摘要	Cancer has been a malignant disease in the worldwide. Therefore, it is urgently to find novel cancer treatments that are effective against multidrug-resistant, dormant or slow-growing cells, while reducing toxicity to patients. In this study, we conduct studies on tumor therapy from two aspects: the regulation of the Wnt/β-catenin signaling pathway in NK cell-mediated tumor immunity; and the anti-tumor activity and mechanism of the Brevinin-1RL1. NKG2D (natural-killer Group 2 member D), an active receptors mainly expressed on the NK cells. By specifically recognized NKG2D ligands to activating NK cells and eliminating target cells. Wnt signaling pathway plays important role in the occurrence and development of colorectal tumors (CRCs) as well as tumor immune regulation. In this study, we investigated the role of the Wnt signaling in NK cell-mediated immune surveillance. The results showed that treatment of CRCs cells with siRNA or small molecule inhibitors significantly increased the expression of NKG2DLs, and enhanced the degranulation and the production of IFN-γ, and promoted the cleavage of NK cells to CRCs. In addition, the killing effect was dependent on the NKG2D receptor-ligand interaction. Molecular mechanism showed that Wnt signaling mainly regulates the expression of NKG2DLs on CRCs through two pathways: TCF4 directly binded to the promoter of NKG2DL and negatively regulated the expression of NKG2DL; activition of Wnt signaling leaded to increased expression of matrix metalloproteinases, thereby promoting the shedding of NKG2DLs. Our results reveal the role of Wnt signaling in NK cell-mediated CRC immunity, and provide new idea for the treatment of CRC. Antimicrobial peptides (AMPs) are small peptides produced in organisms with a variety of biological activities. Studies have shown that AMPs can selectively target tumor cells and exert inhibitory activity. Brevinin-1RL1, a cationic α-helical AMP isolated from frog Rana limnocharis skin secretions. Cell viability assay revealed that Brevinin-1RL1 significantly inhibited the activity of various tumor cells, but had little effect on non-tumor cells. Studies have shown that the disulfide bridge between Brevinin-1RL1 molecules is a key structure for the anticancer activity of Brevinin-1RL1 as deletion of the disulfide bond eliminates the antitumor activity of the peptide. Mechanism studies showed that Brevinin-1RL1 induce Caspase-dependent apoptosis and cell necrosis. Using fluorescence-labeled Brevinin-1RL1, we found that Brevinin-1RL1 mainly aggregated on the surface of tumor cells and tended to act on tumor cells more than non-tumor cells. These results together suggested that Brevinin-1RL1 preferentially converges on the cancer cells to trigger necrosis and apoptosis and could be considered as a pharmacological candidate for further development as anti-cancer agent.
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74499
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	居晓曼. Wnt/β-catenin信号通路调控NK细胞介导的肿瘤免疫和Brevinin-1RL1抗肿瘤研究, Studies of Wnt/β-catenin signaling in NK cell -mediated tumor immunity and anti-tumor of Brevinin-1RL1[D],2021.

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