TrxR抑制剂卟硒啉调节DNA甲基化修饰抑制肿瘤发生的分子机制研究

The thioredoxin reductase/thioredoxin (TrxR/Trx) system has a pivotal role in maintaining the balance of the cellular redox status. The TrxR/Trx system is abnormally activated in various tumors, and is regarded as a classical drug target for the treatment of cancers. Butaselen is a novel anti-tumor drug which has been developed by our research group recently. Our previous findings indicated that butaselen is capable of inhibiting tumorigenesis by targeting TrxR and its downstream effector, such as the NF-κB signaling pathway. However, the specific molecular mechanism of the tumor inhibition induced by butaselen is still unknown. Our recent study showed that butaselen can significantly inhibit the expression of DNA methyltransferase1 (DNMT1). DNMT1 can catalyze DNA methylation on the promoter of tumor suppressor genes (such as p16 and p21), and lead to the silence of tumor suppressor genes, which finally results in tumorigenesis. In this study, we will further investigate whether butaselen could regulate DNA methylation through the TrxR/Trx/HBP1/DNMT1 signaling pathway, and its potential biological function in tumorigenesis inhibition, which will provide theoretical basis for the clinical use of butaselen in the treatment of various cancers.

硫氧还蛋白系统（TrxR/Trx系统）是维持细胞内还原状态的重要调控体系，该体系在人的肿瘤组织中表达显著升高，常作为治疗肿瘤的药物靶标。卟硒啉是以TrxR作为特异性靶标的抗肿瘤药物，关于该创新药物的临床定位研究已经完成，然而，卟硒啉抑制肿瘤发生的具体分子机制尚不十分清楚。我们近期研究发现，卟硒啉能够明显下调DNA甲基转移酶DNMT1的表达。由于DNMT1可以通过提高肿瘤抑制基因启动子区的甲基化修饰水平，达到下调肿瘤抑制基因转录的作用，最终导致肿瘤发生，因而本研究将进一步探讨卟硒啉通过抑制TrxR/Trx下调DNMT1表达的具体分子机制，并明确这一调控作用是否涉及另一种重要的肿瘤抑制因子HBP1，从而为卟硒啉应用于肿瘤的临床治疗提供理论依据，并进一步揭示肿瘤发生的分子机制。