Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse.
Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse.
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DOI：
10.1038/s42003-023-04630-7
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发表时间：
2023-03-08
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
儿童高危肝母细胞瘤(HB)是儿童最常见的肝癌，其预后仍然很差。在本研究中，我们发现核糖核苷酸还原酶(RNR)亚基M2(RRM2)是高危HB中支持细胞增殖的关键基因之一。虽然标准化疗可以有效地抑制HB细胞中的RRM2，但它们诱导了另一种RNRM2亚基RRM2B的显著上调。计算分析表明，RRM2和RRM2B在HB患者肿瘤中参与了不同的信号网络，RRM2支持细胞增殖，RRM2B严重参与应激反应通路。事实上，化疗后HB细胞中RRM2B的上调促进了细胞的存活和随后的复发，在此期间，RRM2B逐渐被RRM2取代。联合应用RRM2抑制剂和化疗可有效延缓体内HB肿瘤复发。总之，我们的研究揭示了两个RNRM2亚基及其动态转换在HB细胞增殖和应激反应中的不同作用。在肝母细胞瘤中，核糖核苷酸还原酶的RRM2亚基与疾病进展有关，但在对化疗的反应中，亚基转换倾向于活性较低的RRM2B亚基，后者支持肝母细胞瘤细胞的存活和复发。
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 (RRM2) 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. In hepatoblastoma, the RRM2 subunit of ribonucleotide reductase is associated with disease progression, but in response to chemotherapy, subunit switching favours the less active RRM2B subunit which supports hepatoblastoma cell survival and relapse.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
3.5
作者：
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影响因子：
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作者：
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通讯作者：
Monga SP
影响因子：
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作者：
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通讯作者：
Hammond EM
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影响因子：
3.4
作者：
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Zeng, Mu-Sheng