Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC
Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC
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DOI：
10.1007/s10495-008-0225-6
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发表时间：
2008-07-01
期刊：
影响因子：
7.2
通讯作者：
Ramp, Uwe
中科院分区：
文献类型：
--
作者：
Heikaus, Sebastian;Kempf, Tobias;Ramp, Uwe
起始半胱天冬酶 - 半胱天冬酶 - 8的激活受到多种抗凋亡调节因子的严格控制，包括ARC、cFlip(S)、cFlip(L)和PED/PEA - 15。由于体内人类肿瘤中关于半胱天冬酶 - 8及其抗凋亡调节因子表达的数据很少，我们分析了它们在肾细胞癌（RCCs）中的表达，以确定这些基因中哪些可能对众所周知的肾细胞癌凋亡受损以及由此导致的对化疗和电离辐射的抗性至关重要。与非肿瘤性肾组织相比，半胱天冬酶 - 8、cFlip(S)、cFlip(L)和PED/PEA - 15的mRNA表达仅在肾细胞癌的早期阶段显著增加。相反，ARC的mRNA表达在所有阶段的肾细胞癌中均显著增加，且肿瘤分期和分级之间无差异。重要的是，在癌变和肿瘤进展过程中，ARC与半胱天冬酶 - 8之间的相对mRNA表达比值显著增加。相比之下，在所有肿瘤阶段，cFlip(S)、cFlip(L)或PED/PEA - 15与半胱天冬酶 - 8之间的相对mRNA表达比值保持恒定。总之，我们的分析表明，ARC是在肾细胞癌中持续过度表达的唯一一种半胱天冬酶 - 8抑制调节因子。此外，抗凋亡的ARC与促凋亡的半胱天冬酶 - 8之间的平衡是在肾细胞癌的癌变和肿瘤进展过程中唯一受到干扰的平衡。因此，这种对半胱天冬酶 - 8的抑制可能是ARC在肾细胞癌中的多种抗凋亡功能的一个例子，可能导致肾细胞癌对放疗和化疗具有显著的抗性，并反映了肾细胞癌中基因表达向更抗凋亡环境的转变。
Activation of the initiator-caspase, caspase-8 is under tight control of multiple antiapoptotic regulators including ARC, cFlip(S), cFlip(L) and PED/PEA-15. Since there is little data regarding the expression of caspase-8 and its antiapoptotic regulators in human tumours in vivo, we analysed their expression in renal cell carcinomas (RCCs) to identify which of these genes might be crucial for the well known impaired apoptosis and-as a result-resistance towards chemotherapy and ionizing radiation of RCCs. Caspase-8, cFlip(S), cFlip(L) and PED/PEA-15 mRNA expression was significantly increased only in early stages of RCCs compared to non-neoplastic renal tissue. In contrast, ARC mRNA expression was significantly increased in RCCs of all stages without differences between the tumour stages and grades. Importantly, the relative mRNA expression ratio between ARC and caspase-8 was significantly increased during carcinogenesis and tumour progression. In contrast, the relative mRNA expression ratio between cFlip(S), cFlip(L) or PED/PEA-15 and caspase-8 remained constant during all tumour stages. In conclusion, our analysis revealed that ARC is the only caspase-8 inhibiting regulator being constantly overexpressed in RCCs. Furthermore, the balance between antiapoptotic ARC and proapoptotic caspase-8 is the only one to be disturbed during carcinogenesis and tumour progression of RCCs. This inhibition of Caspase-8 might therefore be one example for the multiple antiapoptotic functions of ARC in RCCs possibly contributing to the marked resistance of RCCs towards radio- and chemotherapy and reflects a shift of gene expression towards a more antiapoptotic context in RCCs.