核糖核酸酶A家族典型成员在肿瘤发生中的作用

The Roles of the Canonical Members of Ribonuclease A Family in Tumorigenesis

人体中核糖核酸酶A(ribonuclease A,RNaseA)家族包含8个典型成员(RNase 1至RNase 8)。已有研究显示,除RNase 8外,该家族其它典型成员影响了胰腺癌、结直肠癌、膀胱癌、乳腺癌和皮肤癌等多种肿瘤的发生发展。在肿瘤发生过程中,特定RNase表达量及糖基化修饰会发生显著改变,是肿瘤诊断的潜在标志物;它们能以多种机制参与肿瘤发生、生长和转移等过程,有望成为肿瘤治疗的靶点;而部分成员则具有杀伤肿瘤细胞、抑制肿瘤发展的功能,存在临床开发成肿瘤治疗药物的可能。具体而言,RNase 1通过核糖核酸酶活性依赖的细胞毒性和细胞外RNA降解功能,发挥直接杀伤肿瘤细胞或降低局部炎症而抑制肿瘤生长的作用;RNase 1还能结合并激活促红细胞生成素,产生肝细胞癌受体相互作用蛋白A4 (erythropoietin-producing hepatocellular carcinoma receptor-interacting protein A4, EphA4)信号通路,促进乳腺癌的发生。RNase 2和RNase 3是嗜酸性粒细胞颗粒蛋白质的重要成分,依赖于阳离子性及核糖核酸酶活性在抗肿瘤免疫防御中发挥重要作用。RNase 4和RNase 5则通过诱导血管生成、加快肿瘤细胞增殖和抑制肿瘤细胞凋亡等方式,促进肿瘤发生发展。其中RNase 5发挥作用的分子机制包括促进47 S前体rRNA转录和激活促肿瘤生长的信号通路,以及产生tRNA衍生的应激诱导的RNA(tRNA-derived stress-induced RNA,tiRNA)等。虽然RNase 6和RNase 7与肿瘤的发生存在相关性,但其具体作用及机制的研究仍较少。本文总结了RNase A家族典型成员与肿瘤的相关性和作用机制,并对其临床应用前景进行了展望,以期为肿瘤治疗药物的开发提供新思路。

In human,the ribonuclease A(RNase A)family contains 8 canonical members(RNase 1-RNase 8).Research evidence indicated that all the canonical members of this family,except RNase 8,are involved in the occurrence and development of a variety of tumors,including pancreatic cancer,colorectal cancer,bladder cancer,breast cancer,and skin cancer,etc.During tumorigenesis,the expression of specific RNase increased and glycosylation modifications changed,which are potential markers for tumor diagnosis;They also participate in tumor initiation,growth,and metastasis with a variety of mechanisms,and are potential targets for tumor therapy;Meanwhile,some members have the function of killing tumor cells and inhibiting tumor development,and it is possible to develop into tumor therapeutic drugs.Concretely,RNase 1 suppresses tumor growth by directly killing tumor cells or reducing local inflammation through its ribonuclease activity-dependent cytotoxicity and extracellular RNA degradation functions;however,its binding and activation of ephrin A4 signaling pathway promotes breast cancer initiation.RNase 2 and RNase 3 are important components of eosinophil granule proteins that play an important role in anti-tumor immune defense,and their function of killing tumor cells depends on both cationic nature and ribonuclease activity.RNase 4 and RNase 5 can promote tumorigenesis by inducing angiogenesis,promoting tumor cell proliferation,and inhibiting tumor cell apoptosis.The molecular mechanisms of RNase 5 action include promoting the transcription of 47 S precursor rRNA,activating signaling pro-tumor growth signaling pathways,and generating tRNA-derived stress-induced RNA(tiRNA).Besides,RNase 6 and RNase 7 are related to the occurrence of tumors thought their specific role and mechanism are still unclear.In this review,we summarized the relevance and mechanism of RNase A family members on promoting or inhibiting tumors and analyzed their clinical application potentials.