Shi Tongdong, Hu Zaoxiu, Tian Li, Yang Yanlong
Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital of Chongqing Medical University, No.288 Tianwen Avenue, Nan'an District, Chongqing 401336, People's Republic of China.
Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, No.519 Kunzhou Road, Xishan District, Kunming, Yunnan 650118, People's Republic of China.
Transl Oncol. 2023 Aug;34:101691. doi: 10.1016/j.tranon.2023.101691. Epub 2023 May 17.
Lung adenocarcinoma (LUAD) is the most prevalent form of lung cancer globally, and its treatment remains a significant challenge. Therefore, it is crucial to comprehend the microenvironment to improve therapy and prognosis urgently. In this study, we utilized bioinformatic methods to analyze the transcription expression profile of patient samples with complete clinical information from the TCGA-LUAD datasets. To validate our findings, we also analyzed the Gene Expression Omnibus (GEO) datasets. The super-enhancer (SE) was visualized using the peaks of the H3K27ac and H3K4me1 ChIP-seq signal, which were identified by the Integrative Genomics Viewer (IGV). To further investigate the role of Centromere protein O (CENPO) in LUAD, we conducted various assays including Western blot, qRT-PCR, flow cytometry, wound healing and transwell assays to assess the cell functions of CENPO in vitro. The overexpression of CENPO is linked to a poor prognosis in patients with LUAD. Strong signal peaks of H3K27ac and H3K4me1 were also observed near the predicted SE regions of CENPO. CENPO was found to be positively associated with the expression levels of immune checkpoints and drug IC50 value (Roscovitine and TGX221), but negatively associated with the fraction levels of several immature cells and drug IC50 value (CCT018159, GSK1904529A, Lenaildomide, and PD-173074). Additionally, CENPO-associated prognostic signature (CPS) was identified as an independent risk factor. The high-risk group for LUAD is identified based on CPS enrichment, which involved not only endocytosis that transfers mitochondria to promote cell survival in response to chemotherapy but also cell cycle promotion that leads to drug resistance. The removal of CENPO significantly suppressed metastasis and induced arrest and apoptosis of LUAD cells. The involvement of CENPO in the immunosuppression of LUAD provides a prognostic signature for LUAD patients.
肺腺癌（LUAD）是全球最常见的肺癌形式，其治疗仍然是一项重大挑战。因此，迫切需要了解微环境以改善治疗和预后。在本研究中，我们利用生物信息学方法分析了来自TCGA-LUAD数据集的具有完整临床信息的患者样本的转录表达谱。为了验证我们的发现，我们还分析了基因表达综合数据库（GEO）数据集。使用H3K27ac和H3K4me1 ChIP-seq信号峰可视化超级增强子（SE），这些信号峰由综合基因组浏览器（IGV）识别。为了进一步研究着丝粒蛋白O（CENPO）在LUAD中的作用，我们进行了各种实验，包括蛋白质免疫印迹、定量逆转录聚合酶链反应、流式细胞术、伤口愈合实验和Transwell实验，以评估CENPO在体外的细胞功能。CENPO的过表达与LUAD患者的不良预后相关。在CENPO的预测SE区域附近也观察到H3K27ac和H3K4me1的强信号峰。发现CENPO与免疫检查点的表达水平和药物半数抑制浓度（IC50）值（罗可替尼和TGX221）呈正相关，但与几种未成熟细胞的比例水平和药物IC50值（CCT018159、GSK1904529A、来那度胺和PD-173074）呈负相关。此外，CENPO相关预后特征（CPS）被确定为一个独立的危险因素。基于CPS富集确定了LUAD的高危组，这不仅涉及将线粒体转移以促进细胞在化疗反应中存活的内吞作用，还涉及导致耐药性的细胞周期促进作用。去除CENPO可显著抑制LUAD细胞的转移并诱导其停滞和凋亡。CENPO参与LUAD的免疫抑制为LUAD患者提供了一种预后特征。
