DPPA3-HIF1α轴通过引入缓慢的细胞周期表型控制结直肠癌的化疗抗性。
DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype.
发表日期：2023 Aug 01
作者：
Estefania Cuesta-Borràs, Cándida Salvans, Oriol Arqués, Irene Chicote, Lorena Ramírez, Laia Cabellos, Jordi Martínez-Quintanilla, Alex Mur-Espinosa, Alejandro García-Álvarez, Jorge Hernando, Juan Ramón Tejedor, Oriol Mirallas, Elena Élez, Mario F Fraga, Josep Tabernero, Paolo Nuciforo, Jaume Capdevila, Héctor G Palmer, Isabel Puig
来源：
Cell Reports
摘要：
肿瘤复发与快速抗药性紧密相关，是癌症治疗成功的瓶颈。癌细胞通过参与降低增殖状态来绕过治疗诱导的细胞死亡，这是一种非突变机制。通过结合对工程细胞的功能脉冲追踪实验和转录组分析，我们确定了DPPA3作为结直肠癌（CRC）中缓慢周期和抗化疗表型的主要调控因子。我们发现了一个恶性DPPA3-HIF1α反馈循环，通过DNA甲基化下调FOXM1表达，从而延迟细胞周期进程。此外，HIF1α的下调部分恢复了DPPA3过表达癌细胞的化疗敏感性增殖表型。在CRC患者样本队列中，DPPA3过表达作为化疗抗性的预测生物标志物，并且进一步需要其表达的减少才能促进转移性生长。我们的研究表明，慢周期癌细胞利用DPPA3/HIF1α轴在治疗应激下维持肿瘤持续进展，并提供了关于疾病进展的分子调控机制的见解。Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by cancer cells to bypass therapy-induced cell death. Through combining functional pulse-chase experiments in engineered cells and transcriptomic analyses, we identify DPPA3 as a master regulator of slow-cycling and chemoresistant phenotype in colorectal cancer (CRC). We find a vicious DPPA3-HIF1α feedback loop that downregulates FOXM1 expression via DNA methylation, thereby delaying cell-cycle progression. Moreover, downregulation of HIF1α partially restores a chemosensitive proliferative phenotype in DPPA3-overexpressing cancer cells. In cohorts of CRC patient samples, DPPA3 overexpression acts as a predictive biomarker of chemotherapeutic resistance that subsequently requires reduction in its expression to allow metastatic outgrowth. Our work demonstrates that slow-cycling cancer cells exploit a DPPA3/HIF1α axis to support tumor persistence under therapeutic stress and provides insights on the molecular regulation of disease progression.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.