Liu Jinghao, Huang Hua, Han Yueting, Hua Yu, Li Boshi, Liu Hongyu, Chen Jun
Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.
Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
J Cancer. 2024 Jan 16;15(5):1342-1354. doi: 10.7150/jca.91762. eCollection 2024.
Lung adenocarcinoma (LUAD) stands as a prominent subtype within the realm of non-small cell lung cancer and constitutes a primary contributor to cancer-related mortality on a global scale. Notably, hypoxia, a prevalent attribute within solid tumor environments, and mitophagy, a selective manifestation of autophagy dedicated to the removal of damaged mitochondria, have risen to prominence as pivotal factors influencing the initiation and advancement of tumorigenesis. This investigation harnessed publicly accessible genomic datasets encompassing LUAD patients to delineate genes linked to hypoxia and mitophagy, termed hereafter as hypoxia and mitophagy-related genes (HMRGs). Large-scale repositories furnished both gene expression profiles and clinical particulars. The expression profiles of HMRGs were meticulously scrutinized across 1,093 LUAD specimens, leveraging resources such as The Cancer Genome Atlas and Gene Expression Omnibus datasets. A methodical exploration of HMRG patterns within LUAD led to the discernment of two distinct molecular subtypes. Moreover, a discernible correlation emerged between the subtypes and their respective clinical attributes. A risk scoring system was formulated to prognosticate overall survival (OS) and therapeutic responsiveness in LUAD patients. Subsequently, the reliability of this scoring system was authenticated, and a nomogram was adopted to refine the clinical utility range of the risk score. The proliferation and migration impacts of KRT8 on LUAD cells were evaluated through cck8 assays, edu assays, and transwell assays, the results were further validated in vivo. Elevated risk scores were indicative of unfavorable OS probabilities. Furthermore, these risk scores exhibited associations with immune checkpoints and chemotherapeutic drug sensitivity. Collectively, our exhaustive analysis of HMRGs in LUAD patients unveiled their conceivable participation in configuring the multifaceted tumor microenvironment, encompassing clinicopathological attributes and prognosis. A sequence of experiments illuminated the pro-proliferative and pro-migratory attributes of KRT8 in vitro and vivo, thus underscoring its carcinogenic potential. In this study, we have unearthed innovative gene signatures tethered to HMRGs, which harbor prognostic implications concerning patient outcomes. These insights hold potential for steering the development of targeted therapeutic modalities tailored for LUAD.
肺腺癌（LUAD）是非小细胞肺癌领域中的一种主要亚型，是全球癌症相关死亡率的主要贡献因素。值得注意的是，缺氧是实体瘤环境中的一个普遍特征，而线粒体自噬是自噬的一种选择性表现，专门用于清除受损的线粒体，已成为影响肿瘤发生起始和进展的关键因素。本研究利用公开可用的包含LUAD患者的基因组数据集，来描绘与缺氧和线粒体自噬相关的基因，以下称为缺氧和线粒体自噬相关基因（HMRGs）。大规模数据库提供了基因表达谱和临床细节。利用癌症基因组图谱和基因表达综合数据库等资源，对1093例LUAD标本中HMRGs的表达谱进行了细致分析。对LUAD中HMRG模式的系统探索，识别出了两种不同的分子亚型。此外，这些亚型与其各自的临床特征之间存在明显的相关性。制定了一个风险评分系统，以预测LUAD患者的总生存期（OS）和治疗反应性。随后，验证了该评分系统的可靠性，并采用列线图来优化风险评分的临床应用范围。通过cck8检测、edu检测和transwell检测评估了KRT8对LUAD细胞的增殖和迁移影响，并在体内进一步验证了结果。风险评分升高表明OS概率不佳。此外，这些风险评分与免疫检查点和化疗药物敏感性相关。总体而言，我们对LUAD患者中HMRGs的详尽分析揭示了它们可能参与构建多方面的肿瘤微环境，包括临床病理特征和预后。一系列实验阐明了KRT8在体外和体内的促增殖和促迁移特性，从而突出了其致癌潜力。在本研究中，我们发现了与HMRGs相关的创新基因特征，这些特征对患者预后具有预后意义。这些见解有可能指导针对LUAD的靶向治疗模式的开发。
