Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse.
Anthony BrownQingfei PanLi FanÉmilie IndersieCheng TianNikolai TimchenkoLiyuan LiBaranda S HansenHaiyan TanMeifen LuJunmin PengShondra M Pruett-MillerJiyang YuStefano CairoLiqin ZhuPublished in: Communications biology (2023)
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.
Keyphrases
- cell proliferation
- induced apoptosis
- cell cycle
- poor prognosis
- signaling pathway
- pi k akt
- cell cycle arrest
- squamous cell carcinoma
- gene expression
- single cell
- radiation therapy
- oxidative stress
- genome wide
- endothelial cells
- long non coding rna
- electronic health record
- high glucose
- diabetic rats
- dna methylation
- genome wide identification