mRNA清道夫脱帽酶DCPS促进葡萄膜黑色素瘤肝转移及其分子机制的研究

Hepatic metastasis is the major problem in patients with uveal melanoma (UM). Cancer stem-like cells (CSCs) are roots of metastasis, however, the signaling in UM CSCs remains poorly understand. Our preliminary data revealed that mRNA decapping scavenger enzyme (DCPS) was highly overexpressed in UM cells and positively correlated with the hepatic metastasis in patients with UM. Silencing of DCPS by a specific shRNA greatly restrained the self-renewal of UM CSCs and efficiently obviated hepatic metastasis in UM mouse model. These findings provoked us to hypothesize that DCPS might be critical to maintain the self-renewal of UM CSCs to boost the hepatic metastasis in UM. The objective of the study is to validate these hypothesis and clarify the underlying mechanism that DCPS enhanced the self-renewal of UM CSCs to confer hepatic metastasis in UM; observe the blockage effect of specific DCPS shRNA on UM CSCs and hepatic metastasis in UM cells and UM mouse model. Taken together, this study will hopefully corroborate DCPS as a druggable target to therapy of patient with hepatic metastasis in UM and provide a theoretical basis for the application of RG3039 (a selective inhibitor of DCPS) in the treatment of hepatic metastatic UM.

肝转移是葡萄膜黑色素瘤(UM)临床治疗面临的巨大挑战，肿瘤干细胞 (CSCs)在肝脏中的克隆增殖是UM肝转移的根源因素，然而UM CSCs的调控机制尚未得到阐明。我们的前期研究发现，mRNA清道夫脱帽酶DCPS在UM细胞中高表达，DCPS的高表达与UM病人的生存呈负相关，沉默DCPS抑制UM CSCs自我更新及UM肝转移。基于这些前期结果，我们提出了DCPS通过维持UM CSCs自我更新进而促进UM肝转移的科学假设。本课题旨在验证这一科学假设，进一步明确DCPS在维持UM CSCs自我更新及促进UM肝转移中的关键作用，并揭示其分子机制；分别在UM细胞及皮下异种植瘤模型、肝转移模型中明确沉默DCPS对UM CSCs的清除作用及对UM肝转移的抑制作用。本研究预期确认DCPS是UM肝转移的精准干预靶点，并为DCPS选择性抑制剂RG3039应用于治疗UM肝转移的转化医学研究提供理论依据。

肿瘤肝转移是葡萄膜黑色素瘤(Uveal melanoma，UM)临床治疗面临的巨大挑战，肿瘤干细胞(Cancer stem like cells，CSCs)是UM肝转移的根源因素，然而UM CSCs的调控机制尚未完全阐明。通过本项目的实施，我们系统揭示了mRNA清道夫脱帽酶DCPS在UM肝转移中的重要作用，发现DCPS在UM细胞中高表达，DCPS的高表达与UM病人不良预后呈正相关，沉默DCPS抑制UM细胞增殖，DPCS选择性抑制剂RG3039处理抑制UM皮下移植瘤及PDX模型肿瘤的生长。同时，沉默DCPS或RG3039处理下调UM ALDH+细胞比例、抑制UM肿瘤球形成能力、抑制UM细胞迁移及侵袭，并在UM脾-肝转移动物模型中显著克服肝转移。进一步深入研究其分子机制发现，DCPS可维持谷氧还原蛋白(GLRX) 的 mRNA稳定性；沉默或抑制DCPS可降低细胞内还原型谷胱甘肽(GSH)水平，上调UM细胞内活性氧(ROS)含量，进而诱导 UM 细胞发生铁死亡，回补GLRX可显著逆转上述过程。本研究揭示了DCPS-GLRX-Ferroptosis信号轴在UM CSCs干性维持及肝转移中的关键作用，确认DCPS是UM肝转移的潜在精准干预靶点，并为DCPS选择性抑制剂RG3039应用于治疗UM肝转移的转化医学研究提供理论依据。在此基础上，我们进一步发现了细胞周期依赖激酶CDK12是杀伤肿瘤干细胞并克服肿瘤肝转移的成药性新靶标。与本课题相关的研究成果：以共同通讯作者在Clin Transl Med发表SCI论文1篇。课题负责人获批主持国家自然科学基金面上项目1项，深圳市科技创新委员会课题2项，并入选深圳市高层次后备人才。