Erin Nuray, İpekçi Tümay, Akkaya Bahar, Özbudak İrem Hicran, Baykara Mehmet
Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya, Turkey.
Department of Urology, Başkent University, Alanya, Turkey.
Urol Oncol. 2017 Jan;35(1):36.e15-36.e22. doi: 10.1016/j.urolonc.2016.08.010. Epub 2016 Sep 28.
ADAM9, 10, and 17 are a class of disintegrins and metallproteinases with α-secretase activity. There are conflicting results regarding the role(s) of ADAM9, 10, and 17 in carcinogenesis, and only a few studies have examined their levels and cellular localization in renal cell carcinoma (RCC). Studies examining changes in α-secretase activity in RCC compared to enzymatic activity of the uninvolved kidney are lacking.
A cross-sectional study was conducted in 56 patients undergoing radical nephrectomy after the diagnosis of RCC. α-Secretase activity was determined using flourogenic substrate in freshly frozen tumor tissues as well as similarly treated tissues from the neighboring kidney. Immunohistochemical analyses of ADAM9, 10, and 17 were also performed.
α-Secretase activity decreased markedly in all types of RCC as compared to neighboring uninvolved kidney tissue having 5 to 10 times higher levels of α-secretase activity. Although type-dependent variations were observed, tumoral expressions of ADAMs, except for ADAM17, were lower in the tumors compared to that of neighboring tissues, but the changes in α-secretase activity were greater. In RCC tissue, ADAM9 expressions were localized in nuclear and cytoplasmic compartments, whereas ADAM10 and 17 were present predominately in the cytoplasm potentially explaining the markedly decreased enzyme activity. Membranous localization of ADAMs was noted in uninvolved kidney tissue.
The loss of α-secretase activity observed here in conjunction with previous findings argue against tumorigenic effects of ADAM9, 10, and 17 supporting that increased nuclear and cytoplasmic expression may be an attempt to compensate for loss of function.
ADAM9、ADAM10和ADAM17是一类具有α-分泌酶活性的解整合素和金属蛋白酶。关于ADAM9、ADAM10和ADAM17在致癌作用中的角色，存在相互矛盾的结果，并且仅有少数研究检测了它们在肾细胞癌（RCC）中的水平及细胞定位。目前缺乏与未受累肾脏的酶活性相比，RCC中α-分泌酶活性变化的研究。
对56例诊断为RCC后接受根治性肾切除术的患者进行了一项横断面研究。使用荧光底物测定新鲜冷冻肿瘤组织以及来自邻近肾脏的同样处理的组织中的α-分泌酶活性。还对ADAM9、ADAM10和ADAM17进行了免疫组织化学分析。
与α-分泌酶活性水平高5至10倍的邻近未受累肾脏组织相比，所有类型的RCC中α-分泌酶活性均显著降低。尽管观察到了类型依赖性差异，但除ADAM17外，肿瘤中ADAMs的肿瘤表达低于邻近组织，但α-分泌酶活性的变化更大。在RCC组织中，ADAM9表达定位于细胞核和细胞质区室，而ADAM10和ADAM17主要存在于细胞质中，这可能解释了酶活性的显著降低。在未受累的肾脏组织中注意到ADAMs的膜定位。
此处观察到的α-分泌酶活性丧失与先前的研究结果表明，ADAM9、ADAM10和ADAM17不具有致瘤作用，支持细胞核和细胞质表达增加可能是一种功能丧失的补偿机制。
