Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
Department of Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Front Immunol. 2022 Jul 18;13:923031. doi: 10.3389/fimmu.2022.923031. eCollection 2022.
We aimed to characterize serine protease inhibitor Kazal type 1 () as a gene signature for the early diagnosis, molecular targeting, and prediction of immune checkpoint blockade (ICB) treatment response of hepatocellular carcinoma (HCC).
The transcriptomics, proteomics, and phenotypic analyses were performed separately or in combination.
We obtained the following findings on . Firstly, in the transcriptomic training dataset, which included 279 stage I and II tumor samples (out of 1,884 stage I-IV HCC specimens) and 259 normal samples, significantly higher area under curve (AUC) values and increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were demonstrated for HCC discrimination in -associated models compared with those of alpha-fetoprotein (AFP). The calibration of both -related curves fitted significantly better than that of AFP. In the two independent transcriptomic validation datasets, which included 201, 103 stage I-II tumor and 192, 169 paired non-tumor specimens, respectively, the obtained results were consistent with the above-described findings. In the proteomic training dataset, which included 98 stage I and II tumor and 165 normal tissue samples, the analyses also revealed better AUCs and increased IDI and NRI in the aforementioned -associated settings. A moderate calibration was shown for both -associated models relative to the poor results of AFP. Secondly, in the and/or murine models, the wet-lab experiments demonstrated that promoted the proliferation, clonal formation, migration, chemoresistance, anti-apoptosis, tumorigenesis, and metastasis of HCC cells, while the anti- antibody inhibited the growth of the cells, suggesting that has "tumor marker" and "targetable" characteristics in the management of HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that was engaged in immunity-related pathways, including T-cell activation. Thirdly, in the transcriptomic analyses of the 368 HCC specimens from The Cancer Genome Atlas (TCGA) cohort, the high abundance of was positively correlated with the high levels of activated tumor-infiltrating CD4 and CD8 T lymphocytes and dendritic and natural killer cells, while there were also positive correlations between and immune checkpoints, including PD-1, LAG-3, TIM-3, TIGIT, HAVCR2, and CTLA-4. The ESTIMATE algorithm calculated positive correlations between and the immune and ESTIMATE scores, suggesting a close correlation between and the immunogenic microenvironment within HCC tissues, which may possibly help in predicting the response of patients to ICB therapy.
could be a potential biomarker for the early detection, targeted therapy, and prediction of ICB treatment response in the management of HCC.
我们旨在将丝氨酸蛋白酶抑制剂 Kazal 型 1 () 鉴定为基因标志物，用于肝细胞癌 (HCC) 的早期诊断、分子靶向和预测免疫检查点阻断 (ICB) 治疗反应。
分别或联合进行转录组学、蛋白质组学和表型分析。
我们在 中获得了以下发现。首先，在包含 279 例 I 期和 II 期肿瘤样本（1884 例 I-IV HCC 标本中的）和 259 例正常样本的转录组学训练数据集，与 AFP 相比，在与相关模型中 HCC 鉴别中表现出更高的 AUC 值和增加的综合鉴别改善 (IDI) 和净重新分类改善 (NRI)。相关曲线的校准明显好于 AFP。在包含 201 例 I 期和 II 期肿瘤和 192 例配对非肿瘤标本的两个独立转录组学验证数据集以及包含 103 例 I 期和 II 期肿瘤和 169 例配对非肿瘤标本的两个独立转录组学验证数据集，获得的结果与上述发现一致。在包含 98 例 I 期和 II 期肿瘤和 165 例正常组织样本的蛋白质组学训练数据集中，分析还显示，在上述与相关的环境中，AUC 更高，IDI 和 NRI 增加。与 AFP 的较差结果相比，两者的校准均为中度。其次，在和/或模型中，湿实验室实验表明促进了 HCC 细胞的增殖、克隆形成、迁移、化疗耐药、抗凋亡、肿瘤发生和转移，而抗抗体抑制了细胞的生长，这表明在 HCC 的管理中具有“肿瘤标志物”和“可靶向”的特征。基因本体论 (GO) 和京都基因与基因组百科全书 (KEGG) 分析表明，参与了与免疫相关的途径，包括 T 细胞激活。第三，在癌症基因组图谱 (TCGA) 队列的 368 例 HCC 标本的转录组学分析中，的高丰度与激活的肿瘤浸润性 CD4 和 CD8 T 淋巴细胞以及树突状细胞和自然杀伤细胞的高水平呈正相关，同时与免疫检查点，包括 PD-1、LAG-3、TIM-3、TIGIT、HAVCR2 和 CTLA-4 之间也存在正相关。ESTIMATE 算法计算出与免疫和 ESTIMATE 评分之间的正相关，这表明与 HCC 组织内的免疫原性微环境之间存在密切关联，这可能有助于预测患者对 ICB 治疗的反应。
可能是肝细胞癌早期检测、靶向治疗和预测免疫检查点阻断治疗反应的潜在生物标志物。
