Chen Bo, Lu Mengmeng, Chen Qiwen, Zou Enguang, Bo Zhiyuan, Li Jiacheng, Zhao Rui, Zhao Jungang, Yu Zhengping, Chen Gang, Wu Lijun
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Genet. 2024 Jul 26;15:1430885. doi: 10.3389/fgene.2024.1430885. eCollection 2024.
Mitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied.
RNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses.
Two hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817-0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4 T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry.
We found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping.
线粒体功能障碍已被证明在癌症生物学中起关键作用。然而，其在肝内胆管癌（iCCA）中的作用仍未得到充分研究。
从温州医科大学附属第一医院收集30对iCCA及癌旁组织的RNA测序数据。将温州医科大学队列（n = 30）与公共的TCGA（n = 30）和GSE107943（n = 30）数据集整合，建立多中心iCCA队列。我们将TCGA和GSE107943队列合并为一个探索队列，以开发用于预后评估的线粒体特征，并利用温州医科大学队列进行外部验证。使用基因本体论（GO）、京都基因与基因组百科全书（KEGG）和标志性分析对iCCA相关的线粒体相关基因（MRG）进行功能解释。此外，利用三个机构的数据进行无监督聚类，以识别基于线粒体的iCCA亚型。进一步研究线粒体功能障碍对药物反应、肿瘤免疫微环境改变和免疫反应的影响。
鉴定出263个与iCCA相关的MRG，它们与脂肪酸代谢、氧化磷酸化和细胞凋亡有关。通过单变量和多变量Cox分析以及LASSO分析，建立了一个包含五个最佳MRG的线粒体特征，用于评估iCCA患者的预后，在探索队列中AUC值范围为0.785至0.928。该特征在温州医科大学队列中也表现出令人满意的性能，AUC值为0.817 - 0.871，并且在两个队列中均被确定为独立的风险预测因子。此外，我们发现线粒体评分较高且预后较差的患者CD4 T细胞、NK细胞和单核细胞的浸润水平较低，并且对包括索拉非尼在内的靶向治疗表现出更高的敏感性。此外，确定了两种不同的基于线粒体的亚型，亚型2与较短的生存时间和免疫抑制性肿瘤微环境相关。最后，通过免疫组织化学验证了五个关键MRG的差异蛋白表达。
我们发现线粒体功能障碍调节iCCA中的异常代谢、氧化应激、免疫反应、细胞凋亡和药物敏感性。鉴定出一个线粒体特征和两种基于线粒体的iCCA亚型，用于临床风险分层和免疫表型分析。
