USP22/HIF1α正反馈调节机制促进肝细胞肝癌干性的研究

Drug resistance, tumor metastasis, and recurrence are the main reasons for hepatocellular carcinoma (HCC) systemic therapy failure, and complex biological mechanisms are involved. Thus, identification of target molecules that control the biological characteristics of HCC is great important to explore novel therapeutic strategy of HCC. Targeting cancer stemness is becoming an important strategy to overcome drug resistance and to suppress tumor metastasis and recurrence currently. Our recently study found that in HCC cells, an interaction was between ubiquitin-specific protease 22 (USP22) and hypoxia inducible factor 1 subunit alpha (HIF-1α), those are two molecules possibly involving in the maintenance of cancer stemness. We found that there is a potential positive feedback loop between USP22 and HIF-1α. However, the detail mechanism underlines the interaction of these two molecules and the role of role of USP22/HIF1α in maintaining HCC stemness phenotypes are unclear. In this study, we aim to try to clarify the molecular regulation mechanisms between USP22 and HIF-1α and correlate it with the expression pattern of USP22, HIF-1α and other cancer stem cell markers in clinical HCC samples. We also aim to uncover the role of the interaction of USP22 and HIF1α in maintaining HCC stemness phenotypes. Finally, this research may prove the crucial role of the interaction between USP22 and HIF1α in maintaining cancer stemness of HCC and targeting the interaction of USP22 and HIF1α is potentially utilized for developing new therapeutic strategy of HCC.

肝细胞肝癌的发生机制十分复杂且极易发生肿瘤耐药、转移和复发，严重限制了已有治疗手段的应用和疗效。寻找更加精准有效的治疗靶点，是提高肝细胞肝癌治疗效果的关键。目前，靶向肿瘤干性已成为克服肿瘤耐药、抑制肿瘤转移与复发的重要策略之一。项目组前期研究发现，与肿瘤干性相关的去泛素化蛋白酶USP22和缺氧诱导因子1-α（HIF-1α）在肝癌细胞中存在正反馈调控，但具体调控机制及其对肿瘤干性表型的影响尚不清楚。本项目拟在分子层面解析USP22和HIF-1α的互作机制，并评价二者间的互作对肝细胞肝癌干性表型的影响；同时，结合对肝癌组织标本中USP22、HIF-1α及其他细胞干性相关标志蛋白的表达特征分析，进一步佐证所揭示的分子调控机制。以上研究的开展，将明确USP22和HIF-1α在促进肝细胞肝癌干性表型中的关键作用，并作为潜在靶点用于探索肝细胞肝癌治疗的新策略。

肿瘤组织中某些细胞亚群的干细胞特性被认为与肿瘤的发生、侵袭转移、血管新生和放化疗抵抗密切相关, 靶向肿瘤干细胞特性已成为克服肿瘤细胞耐药、抑制肿瘤转移与复发的重要策略。该研究发现，去泛素化蛋白酶 ubiquitin-specific protease 22(USP22) 可在缺氧条件下稳定肝癌细胞中的HIF1α蛋白；而在TP53失活的肝癌细胞中，HIF1α可促进USP22的转录表达。USP22与HIF1α组成的正反馈调节通路可促进肝癌细胞的干性表型。分析肝癌病人的组织标本发现，TP53失活突变合并USP22和HIF1α高表达的患者预后更差。TP53失活突变是肝癌发生发展中的常见事件，与肝癌的恶性生物学行为密切相关。该研究解析了USP22/HIF1α调控环路在TP53失活突变肝癌中的关键作用，揭示了维持肝癌干性的全新分子通路。另外，鉴于目前缺少USP22的特异性抑制剂，该团队开发了一种新型肿瘤内活性氧响应的纳米基因药物，特异性降低肿瘤内USP22的表达，可显著抑制肝癌肿瘤的生长，并且增强肝癌细胞对索拉菲尼的敏感性，为肝癌的精准靶向治疗提供了有效的策略。