Chen Ting-Wen, Chang Kai-Ping, Cheng Chun-Chia, Chen Cheng-Yi, Hong Shu-Wen, Sie Zong-Lin, Cheng Hsing-Wen, Yen Wei-Chen, Huang Yenlin, Liu Shu-Chen, Wang Chun-I
Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan.
Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan.
Cancers (Basel). 2021 Nov 10;13(22):5623. doi: 10.3390/cancers13225623.
Radioresistance is one of the major factors that contributes to radiotherapy failure in oral cavity squamous cell carcinoma (OSCC). By comparing the prognostic values of 20,502 genes expressed in patients in The Cancer Genome Atlas (TCGA)-OSCC cohort with ( = 162) and without radiotherapy ( = 118), herein identified 297 genes positively correlated with poor disease-free survival in OSCC patients with radiotherapy as the potential radioresistance-associated genes. Among the potential radioresistance-associated genes, 36 genes were upregulated in cancerous tissues relative to normal tissues. The bioinformatics analysis revealed that 60S ribosomal protein L36a (RPL36A) was the most frequently detected gene involved in radioresistance-associated gene-mediated biological pathways. Then, two independent cohorts ( = 162 and = 136) were assessed to confirm that higher RPL36A transcript levels were significantly associated with a poor prognosis only in OSCC patients with radiotherapy. Mechanistically, we found that knockdown of RPL36A increased radiosensitivity via sensitizing cells to DNA damage and promoted G2/M cell cycle arrest followed by augmenting the irradiation-induced apoptosis pathway in OSCC cells. Taken together, our study supports the use of large-scale genomic data for identifying specific radioresistance-associated genes and suggests a regulatory role for RPL36A in the development of radioresistance in OSCC.
放射抗性是导致口腔鳞状细胞癌（OSCC）放疗失败的主要因素之一。通过比较癌症基因组图谱（TCGA）-OSCC队列中接受放疗（n = 162）和未接受放疗（n = 118）患者所表达的20502个基因的预后价值，在此确定了297个与接受放疗的OSCC患者无病生存期差呈正相关的基因，作为潜在的放射抗性相关基因。在潜在的放射抗性相关基因中，相对于正常组织，有36个基因在癌组织中上调。生物信息学分析显示，60S核糖体蛋白L36a（RPL36A）是参与放射抗性相关基因介导的生物学途径中最常检测到的基因。然后，评估了两个独立队列（n = 162和n = 136），以确认仅在接受放疗的OSCC患者中，较高的RPL36A转录水平与不良预后显著相关。从机制上讲，我们发现敲低RPL36A通过使细胞对DNA损伤敏感来增加放射敏感性，并促进G2/M细胞周期阻滞，随后增强OSCC细胞中辐射诱导的凋亡途径。综上所述，我们的研究支持利用大规模基因组数据来识别特定的放射抗性相关基因，并表明RPL36A在OSCC放射抗性发展中具有调节作用。
