Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Cancer Genomics Proteomics. 2024 Mar-Apr;21(2):158-165. doi: 10.21873/cgp.20437.
BACKGROUND/AIM: The prognosis of patients with malignant pleural mesothelioma (MPM) remains poor due to lack of effective therapeutic targets. DNA damage caused by long-time exposure to asbestos fibers has been associated with the development of MPM, with mutations at genes encoding DNA damage repair (DDR)-related molecules frequently expressed in patients with MPM. The present study was designed to identify novel therapeutic targets in MPM using large public databases, such as The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) focused on DDR pathways.
The correlations between mRNA expression levels of DDR-related genes and overall survival (OS) were analyzed in mesothelioma patients in TCGA mesothelioma (TCGA-MESO) datasets. The anti-tumor effects of small interfering RNAs (siRNA) against DDR-related genes associated with OS were subsequently tested in MPM cell lines.
High levels of mRNA encoding DNA polymerase delta 1, catalytic subunit (POLD1) were significantly associated with reduced OS in patients with MPM (p<0.001, Log-rank test). In addition, siRNA targeting POLD1 (siPOLD1) caused cell cycle arrest at the G/S checkpoint and induced apoptosis involving accumulation of DNA damage in MPM cell lines.
POLD1 plays essential roles in overcoming DNA damage and cell cycle progression at the G/S checkpoint in MPM cells. These findings suggest that POLD1 may be a novel therapeutic target in MPM.
背景/目的：由于缺乏有效的治疗靶点，恶性胸膜间皮瘤（MPM）患者的预后仍然很差。长时间暴露于石棉纤维引起的 DNA 损伤与 MPM 的发生有关，MPM 患者常表达编码 DNA 损伤修复（DDR）相关分子的基因突变。本研究旨在使用大型公共数据库（如聚焦于 DDR 通路的癌症基因组图谱（TCGA）和基因型组织表达项目（GTEx））鉴定 MPM 中的新治疗靶点。
在 TCGA 间皮瘤（TCGA-MESO）数据集的间皮瘤患者中，分析 DDR 相关基因的 mRNA 表达水平与总生存期（OS）之间的相关性。随后在 MPM 细胞系中测试与 OS 相关的 DDR 相关基因的小干扰 RNA（siRNA）的抗肿瘤作用。
高水平的 DNA 聚合酶 delta 1，催化亚基（POLD1）mRNA 编码与 MPM 患者的 OS 降低显著相关（p<0.001，对数秩检验）。此外，靶向 POLD1 的 siRNA（siPOLD1）导致 MPM 细胞系中细胞周期停滞在 G/S 检查点，并诱导涉及 DNA 损伤积累的细胞凋亡。
POLD1 在 MPM 细胞中克服 DNA 损伤和 G/S 检查点的细胞周期进展中起重要作用。这些发现表明 POLD1 可能是 MPM 的一个新的治疗靶点。
