背景:肝细胞癌(HCC)是全球癌症相关死亡的第三大原因,其特点是发病隐秘,快速发展,预后不良。免疫治疗是晚期肝癌的一线治疗方法。免疫相关预后标志物的鉴定可能是预测和提高免疫治疗临床反应率的有效策略。
方法:DESeq2,edgeR,和limmaR包用于比较具有不同预后的HCC的转录组。与癌症相关的数据库,如UALCAN,TNMplot,GEPIA,muttarget和人类蛋白质图谱(HPA),采用Kaplan-MeierPlotter平台分析CLDN18与临床特征的关系,以及HCC的预后。CLDN18的共表达基因从LinkedOmics平台获得,并进行了GO功能富集和KEGG通路分析。TheCIBERSORT,TIMER,Timer2.0和TISIDB算法用于分析免疫浸润。
结果:CLDN18在不同预后的HCC患者中差异表达,PBMC表达水平与BCLC分期呈正相关。此外,与邻近的非肿瘤组织相比,CLDN18在HCC肿瘤组织中显著过表达,这与PBMC测序结果和人类蛋白质谱的免疫组织化学数据一致。CLDN18也与HCC分期和分级呈正相关,CLDN18的高表达水平预测总生存期较短。CLDN18在HCC中的功能注释揭示了细胞衰老和蛋白质活化级联的富集,以及细胞周期等生物过程,炎症反应,和细胞酮代谢。此外,CLDN18也与肿瘤浸润免疫细胞有关,抑制性免疫细胞标记,T淋巴细胞耗竭和肝癌的激活,CLDN18的低表达与较高的CD8+T细胞浸润和较高的生存率相关。
结论:CLDN18是HCC潜在的预后标志物和免疫治疗靶点。
BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and is characterized by insidious onset, rapid progression, and poor prognosis. Immunotherapy is a first-line treatment for advanced HCC. The identification of immune-related prognostic markers may be an effective strategy to predict and improve clinical response rate of immunotherapy.
METHODS: The DESeq2, edgeR, and limma R packages were used to compare the transcriptomes of HCC with different prognoses. Cancer-related databases such as UALCAN, TNMplot, GEPIA, muttarget and Human Protein Atlas (HPA), and the Kaplan-Meier Plotter platform were used to analyze the relationship between CLDN18 and the clinical characteristics, as well as prognosis of HCC. The co-expressed genes of
CLDN18 were obtained from LinkedOmics platform, and GO functional enrichment and KEGG pathway analysis were performed. The CIBERSORT, TIMER, Timer 2.0 and TISIDB algorithms were used to analyze immune infiltration.
RESULTS: CLDN18 was differentially expressed in HCC patients with different prognoses, and its expression level in PBMC was positively correlated with the stage of BCLC. In addition, CLDN18 was significantly overexpressed in HCC tumor tissues compared to adjacent non-tumor tissues, which was consistent with PBMC sequencing results and immunohistochemical data from human protein profiles.
CLDN18 was also positively correlated with HCC staging and grading, and high expression levels of
CLDN18 predicted shorter overall survival. Functional annotation of CLDN18 in HCC revealed enrichment of the cellular senescence and protein activation cascade, along with biological processes such as cell cycle, inflammatory response, and cellular ketone metabolism. In addition,
CLDN18 was also associated with tumor infiltrating immune cells, suppressive immune cell markers, T lymphocyte depletion and activation of HCC, and low expression of CLDN18 was associated with higher CD8 + T cell infiltration and better survival rates.
CONCLUSIONS: CLDN18 is a potential prognostic marker and immunotherapeutic target for HCC.