Brown Anthony, Pan Qingfei, Fan Li, Indersie Emilie, Tian Cheng, Timchenko Nikolai, Li Liyuan, Hansen Baranda S, Tan Haiyan, Lu Meifen, Peng Junmin, Pruett-Miller Shondra M, Yu Jiyang, Cairo Stefano, Zhu Liqin
bioRxiv. 2023 Jan 24:2023.01.24.525404. doi: 10.1101/2023.01.24.525404.
Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 ( ) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B . Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.
高危型肝母细胞瘤（HB）是最常见的儿童肝癌，其患儿的预后仍然很差。在本研究中，我们发现核糖核苷酸还原酶（RNR）亚基M2（ ）是支持高危型HB细胞增殖的关键基因之一。虽然标准化疗可以有效抑制HB细胞中的RRM2，但它们会导致另一个RNR M2亚基RRM2B显著上调。计算分析表明，RRM2和RRM2B参与HB患者肿瘤的不同信号网络，其中RRM2支持细胞增殖，而RRM2B大量参与应激反应途径。事实上，化疗处理的HB细胞中RRM2B的上调促进了细胞存活及随后的复发，在此过程中RRM2B逐渐被RRM2取代。在体内将RRM2抑制剂与化疗联合使用可有效延迟HB肿瘤复发。总体而言，我们的研究揭示了两个RNR M2亚基在HB细胞增殖和应激反应中的不同作用及其动态转换。
