靶向DNA复制起始蛋白的共同转录因子PAX2治疗癌症 Targeting PAX2, a common transcriptional regulator of DNA replication-initiation proteins, for treating cancer

癌症是危及我国人民健康的重大疾病。现有药物抗癌效果并不理想。DNA复制起始蛋白（DRIPs）被认为是癌症治疗的靶标，但DRIPs种类多，其中一些DRIPs功能相互补偿，靶向单一DRIP可能无法抑制肿瘤细胞DNA复制。我们前期体内外研究及RNA-Seq分析发现，具有协同抗黑色素瘤作用的两个化合物联用能降低肿瘤细胞中多个DRIPs的mRNA水平。转录因子结合位点分析表明，配对盒因子2（PAX2）可能是DRIPs的一个共同转录因子。Western blot检测发现，两个化合物联用可降低黑色素瘤细胞核中PAX2的蛋白水平。重要的是，沉默PAX2能显著下调黑色素瘤细胞中DRIPs的mRNA水平，并抑制黑色素瘤和肝癌细胞增殖、导致细胞周期阻滞、促进癌细胞凋亡。由此我们推测PAX2是DRIPs的共同转录因子，靶向PAX2以下调DRIPs表达可能是一个癌症治疗新策略。本研究将进一步证实PAX2是DRIPs共同转录因子；在体内外模型上验证PAX2是癌症治疗的靶标，并证实抑制PAX2抗癌的机制与下调DRIPs表达有关。本项目研究结果将为靶向PAX2治疗癌症奠定生物学基础。
Cancer is a major disease that poses a threat to the health of people in China. The current clinical outcomes of drug therapies for cancer are not satisfactory. DNA replication-initiation proteins (DRIPs) have been identified as targets for treating cancer. However, there are various types of DRIPs, some of which may compensate for each other functionally. Targeting a single DRIP may not be able to inhibit DNA replication in tumor cells. Our preliminary data have found that a combination of two compounds has synergistic anti-melanoma effects. Analysis of RNA-Seq results indicates that this combination downregulates the expression of a series of DRIPs in melanoma cells. Transcription factor binding site analysis suggests that paired box gene 2 (PAX2) may be a common transcription factor for DRIPs. Western blot results have shown that the combination of two compounds can lower the protein level of PAX2 in the nuclei of melanoma cells. Notably, silencing PAX2 can significantly reduce the mRNA levels of multiple DRIPs in melanoma cells, and inhibit the proliferation of, induce cell cycle arrest and cell apoptosis in, melanoma and liver cancer cells. Based on this, we hypothesize that PAX2 is a common transcription factor for DRIPs, and targeting PAX2 to downregulate DRIPs’ expression could be a novel strategy for treating cancer. This study will further validate that PAX2 is a common transcription factor for DRIPs, and establish PAX2 as a target for cancer therapy in both in vivo and in vitro models. This work will demonstrate that inhibition of PAX2 exerts anti-cancer effects by downregulating the expression of DRIPs. The findings of this project will lay the biological foundation for targeting PAX2 in cancer treatment.