Disoma Cyrollah, Tiribelli Claudio, Sukowati Caecilia
Doctoral School of Molecular Biomedicine, Department of Life Sciences, University of Trieste, 34149 Trieste, Italy; Liver Cancer Unit, Fondazione Italiana Fegato ONLUS (Italian Liver Foundation NPO), AREA Science Park Basovizza, 34149 Trieste, Italy.
Liver Cancer Unit, Fondazione Italiana Fegato ONLUS (Italian Liver Foundation NPO), AREA Science Park Basovizza, 34149 Trieste, Italy.
Ann Hepatol. 2025 Jun 1;30(2):101932. doi: 10.1016/j.aohep.2025.101932.
Liver cancer is the sixth most common malignancy and the third leading cause of cancer-related deaths globally. Hepatocellular carcinoma (HCC) is the most prevalent type, accounting for nearly 90 % of all liver cancer cases. The first-line systemic therapy for advanced HCC includes lenvatinib, an oral multi-kinase tyrosine inhibitor. However, many HCC patients exhibit resistance to lenvatinib, leading to treatment failure. Recent studies suggest that lenvatinib resistance is multi-factorial.
Four public RNA-seq datasets were retrieved from Gene Expression Omnibus (GEO) database and further analyzed to identify novel gene drivers of lenvatinib resistance. Bioinformatics analyses were performed in differentially expressed genes. In vitro validation was conducted in HCC cell lines after acute lenvatinib treatment.
After applying several filtering conditions, Gene Ontology (GO) and pathway enrichment analyses using Kyoto Encyclopaedia of Genes and Genome (KEGG) databases to identify significantly enriched pathways, a total of five genes emerged as good novel candidate genes which are likely to be associated with lenvatinib resistance: SEZ6L2, SECTM1, FBLN7, IFI6, and NPC1L1. The association of these five genes with patient's prognosis was based on TCGA database. Our validation using Huh7 and Hep3B HCC cells treated with lenvatinib showed increased consistent mRNA expressions of SECTM1 and IFI6.
This study showed the relevance of finding new genes associated with lenvatinib resistance.
肝癌是全球第六大常见恶性肿瘤，也是癌症相关死亡的第三大主要原因。肝细胞癌（HCC）是最常见的类型，占所有肝癌病例的近90%。晚期HCC的一线全身治疗包括乐伐替尼，一种口服多激酶酪氨酸抑制剂。然而，许多HCC患者对乐伐替尼表现出耐药性，导致治疗失败。最近的研究表明，乐伐替尼耐药是多因素的。
从基因表达综合数据库（GEO）中检索了四个公共RNA测序数据集，并进一步分析以确定乐伐替尼耐药的新基因驱动因素。对差异表达基因进行生物信息学分析。在急性乐伐替尼治疗后的HCC细胞系中进行体外验证。
在应用多个筛选条件后，使用京都基因与基因组百科全书（KEGG）数据库进行基因本体论（GO）和通路富集分析以识别显著富集的通路，共有五个基因成为可能与乐伐替尼耐药相关的良好新候选基因：SEZ6L2、SECTM1、FBLN7、IFI6和NPC1L1。这五个基因与患者预后的关联基于TCGA数据库。我们使用乐伐替尼处理的Huh7和Hep3B HCC细胞进行的验证显示，SECTM1和IFI6的mRNA表达一致性增加。
本研究表明了寻找与乐伐替尼耐药相关新基因的相关性。
