去整合素和金属蛋白酶结构域10(ADAM10),ADAM家族的一员,是具有潜在粘附和蛋白酶/转化酶功能的细胞表面蛋白。天然产物[腺苷(AD)及其类似物在癌症中的表达调控,虫草素(CD),和N6,N6-二甲基腺苷(m62A)],和免疫调节还不清楚。作为结果,AD,CD,m62A抑制ADAM10在各种癌细胞系中的表达,表明它们在抗癌药物中的作用。与ADAM10蛋白进一步的分子对接发现,所有小分子的所有对接基团的结合能均<-7kcal/mol(AD,CD和m62A),提出了非常好的绑定活动。此外,对肿瘤免疫调节作用的分析表明,ADAM10与免疫调节基因如CCL27、CCL14、CCL25、CXCR5、HLA-B、HLA-DOB1,LAG3,TNFRSF18和TNFRSF4在膀胱尿路上皮癌中,胸腺瘤,乳腺浸润性癌,TGCT,肾乳头状细胞癌,SKCM与甲状腺癌,表明ADAM10的免疫促进作用。体内AD和CD均降低了LAG3mRNA水平。ADAM10还与肿瘤免疫抑制呈负相关,并与肿瘤的免疫浸润相关。总的来说,本研究确定了AD的ADAM10表达,CD和m62A,在癌症中的AD或CD/ADAM10/LAG3信号传导中,并提出了一种使用小分子AD靶向ADAM10的癌症免疫治疗的潜在方法,CD和m62A。
A disintegrin and metalloproteinase domain 10 (ADAM10), a member of the ADAM family, is a cellular surface protein with potential adhesion and protease/convertase functions. The expression regulations in cancers by natural products [adenosine (AD) and its analogs, cordycepin (CD), and N6, N6-dimethyladenosine (m6 2A)], and immune regulation are unclear. As results, AD, CD, and m6 2A inhibited ADAM10 expression in various cancer cell lines, indicating their roles in anti-cancer agents. Further molecular docking with ADAM10 protein found the binding energies of all docking groups were <-7 kcal/mol for all small-molecules (AD, CD and m6 2A), suggesting very good binding activities. In addition, analysis of the immunomodulatory roles in cancer showed that ADAM10 was negatively correlated with immunomodulatory genes such as CCL27, CCL14, CCL25, CXCR5, HLA-B, HLA-DOB1, LAG3, TNFRSF18, and TNFRSF4 in bladder urothelial carcinoma, thymoma, breast invasive carcinoma, TGCT, kidney renal papillary cell carcinoma, SKCM and thyroid carcinoma, indicating the immune-promoting roles for ADAM10. LAG3 mRNA levels were reduced by both AD and CD in vivo. ADAM10 is also negatively associated with tumor immunosuppression and interrelated with the immune infiltration of tumors. Overall, the present study determined ADAM10 expression by AD, CD and m6 2A, and in AD or CD/ADAM10/LAG3 signaling in cancers, and suggested a potential method for immunotherapy of cancers by targeting ADAM10 using the small molecules AD, CD and m6 2A.