Pan Dong, Du Yarong, Li Rong, Shen Aihua, Liu Xiaodong, Li Chuanyuan, Hu Burong
Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Space Radiobiology of Gansu Province, Institute of Modern Physics, Chinese Academy of Sciences (CAS), Lanzhou, China.
Front Cell Dev Biol. 2021 Sep 16;9:741074. doi: 10.3389/fcell.2021.741074. eCollection 2021.
Radioresistance conferred by cancer stem cells (CSCs) is the principal cause of the failure of cancer radiotherapy. Eradication of CSCs is a prime therapeutic target and a requirement for effective radiotherapy. Three dimensional (3D) cell-cultured model could mimic the morphology of cells and induce CSC properties. Emerging evidence suggests that microRNAs (miRNAs) play crucial roles in the regulation of radiosensitivity in cancers. In this study, we aim to investigate the effects of miRNAs on the radiosensitivity of 3D cultured stem-like cells. Using miRNA microarray analysis in 2D and 3D cell culture models, we found that the expression of miR-29b-3p was downregulated in 3D cultured A549 and MCF7 cells compared with monolayer (2D) cells. Clinic data analysis from The Cancer Genome Atlas database exhibited that miR-29b-3p high expression showed significant advantages in lung adenocarcinoma and breast invasive carcinoma patients' prognosis. The subsequent experiments proved that miR-29b-3p overexpression decreased the radioresistance of cells in 3D culture and tumors through interfering kinetics process of DNA damage repair and inhibiting oncogenes RBL1, PIK3R1, AKT2, and Bcl-2. In addition, miR-29b-3p knockdown enhanced cancer cells invasion and migration capability. MiR-29b-3p overexpression decreased the stemness of 3D cultured cells. In conclusion, our results demonstrate that miR-29b-3p could be a sensitizer of radiation killing in CSC-like cells inhibiting oncogenes expression. MiR-29b-3p could be a novel therapeutic candidate target for radiotherapy.
癌症干细胞（CSCs）赋予的放射抗性是癌症放射治疗失败的主要原因。根除癌症干细胞是主要的治疗靶点，也是有效放射治疗的必要条件。三维（3D）细胞培养模型可以模拟细胞形态并诱导癌症干细胞特性。新出现的证据表明，微小RNA（miRNAs）在癌症放射敏感性的调节中起关键作用。在本研究中，我们旨在研究miRNAs对3D培养的干细胞样细胞放射敏感性的影响。通过在2D和3D细胞培养模型中进行miRNA微阵列分析，我们发现与单层（2D）细胞相比，miR-29b-3p在3D培养的A549和MCF7细胞中的表达下调。来自癌症基因组图谱数据库的临床数据分析显示，miR-29b-3p高表达在肺腺癌和乳腺浸润性癌患者的预后方面具有显著优势。随后的实验证明，miR-29b-3p过表达通过干扰DNA损伤修复的动力学过程并抑制癌基因RBL1、PIK3R1、AKT2和Bcl-2，降低了3D培养细胞和肿瘤的放射抗性。此外，miR-29b-3p敲低增强了癌细胞的侵袭和迁移能力。miR-29b-3p过表达降低了3D培养细胞的干性。总之，我们的结果表明，miR-29b-3p可能是抑制癌基因表达的CSC样细胞中辐射杀伤的增敏剂。miR-29b-3p可能是放射治疗的新型候选治疗靶点。
