Xu Junxiu, Zhang Kai, Zhang Genhao
Department of Medical Laboratory, Zhengzhou University Fifth Affiliated Hospital, Zhengzhou, People's Republic of China.
Department of Medical Laboratory, Zhengzhou University Third Affiliated Hospital, Zhengzhou, People's Republic of China.
J Hepatocell Carcinoma. 2023 Mar 21;10:459-472. doi: 10.2147/JHC.S401338. eCollection 2023.
Lysosomes play an important role in enhancing tumorigenesis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, a detailed analysis of the role of lysosome-related genes could improve the poor prognosis of HCC patients.
Lysosome-associated genes were downloaded from the GO and Genome Enrichment Analysis (GSEA) databases. After analyzing lysosome-associated differentially expressed genes (DEGs) between the TCGA and GTEx cohorts, we used univariate Cox regression, LASSO-Cox regression, stepwise Cox regression, and multivariate Cox regression analyses to build a predictive risk model. The ICGC cohort was used as a test cohort for the prognostic signature's validation. It was also assessed how significantly the signature affected the tumor microenvironment (TME) and sensitivity to immune checkpoint inhibitors. To investigate the expression of this signature in clinical samples, qRT-PCR and immunohistochemistry (IHC) were carried out in 50 normal tissues and 59 HCC tissues.
A total of 894 lysosome-associated genes were obtained. After identifying 113 lysosome-associated DEGs, we constructed a five-gene prognostic signature (RRAGD, AP1M2, CRHBP, NCSTN, and SLCO4C1) that can be effectively applied to the prognostic classification of HCC patients in TCGA and ICGC cohorts. Additionally, we discovered that this signature can affect the proportion of macrophage infiltration in TME. We also evaluated several tumor-sensitive medicines that affect this signature. Finally, we discovered that HCC tissues had lower amounts of CRHBP compared to normal tissues by the qRT-PCR and IHC assay.
We developed and validated a predictive signature of five lysosome-related genes for HCC patients and verified the downregulation of CRHBP expression in clinical samples, which may provide fresh perspectives for customized immunotherapy.
溶酶体在增强肝细胞癌（HCC）的肿瘤发生和化疗耐药性方面发挥着重要作用。因此，详细分析溶酶体相关基因的作用可能会改善HCC患者的不良预后。
从GO和基因组富集分析（GSEA）数据库中下载溶酶体相关基因。在分析TCGA和GTEx队列之间的溶酶体相关差异表达基因（DEG）后，我们使用单变量Cox回归、LASSO-Cox回归、逐步Cox回归和多变量Cox回归分析来构建预测风险模型。ICGC队列用作预后特征验证的测试队列。还评估了该特征对肿瘤微环境（TME）和免疫检查点抑制剂敏感性的影响程度。为了研究该特征在临床样本中的表达情况，对50个正常组织和59个HCC组织进行了qRT-PCR和免疫组织化学（IHC）检测。
共获得894个溶酶体相关基因。在鉴定出113个溶酶体相关DEG后，我们构建了一个五基因预后特征（RRAGD、AP1M2、CRHBP、NCSTN和SLCO4C1），该特征可有效应用于TCGA和ICGC队列中HCC患者的预后分类。此外，我们发现该特征可影响TME中巨噬细胞浸润的比例。我们还评估了几种影响该特征的肿瘤敏感药物。最后，通过qRT-PCR和IHC检测发现，与正常组织相比，HCC组织中CRHBP的含量较低。
我们开发并验证了一种针对HCC患者的五个溶酶体相关基因的预测特征，并在临床样本中验证了CRHBP表达的下调，这可能为定制免疫治疗提供新的视角。
