Department of Radiology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
Department of Integrated Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
Environ Toxicol. 2024 Feb;39(2):612-625. doi: 10.1002/tox.23904. Epub 2023 Jul 29.
As the sixth most common type of cancer worldwide, liver hepatocellular carcinoma (LIHC) emerges as grave public health danger owing to its chemotherapy-resistant feature. Disulfidoptosis is a newly discovered programmed cell death process affecting the normal actin cytoskeleton structure.
Single-cell RNA (scRNA)-seq data were procured from GSE149614 and GSE202642 datasets. We utilized uniform manifold approximation and projection and clustering algorithm Louvian for dimensionality reduction and FindAllMarkers function for determining the differentially expressed genes (DEGs). Monocle2 and SCENIC were utilized to perform pseudo-time series and transcription factor analysis for selected subgroups. A series of in vitro experiments, including colony formation assay (CFA), flow cytometry targeting apoptosis and cell cycle, was applied to investigate how APLP2 regulated the LIHC progression. Two cell lines of LIHC cells, HepG2, and Huh7, were used for si-APLP2 transfection.
Tumor heterogeneity landscape of LIHC was depicted by detailed subgroup analysis. We found T and B cells were enriched with POU2F1 and HES1 activity. Inflammatory cancer-associated fibroblasts interacted with the cancer cells, uniquely through COL1A1/SDC1, COL1A2/SDC1 and LUM/ITGB1 pathways. The transformation from normal hepatocytes to malignant cells was displayed by cell trajectory analysis. State4, which was determined as malignant cells, was enriched in PI3K, hypoxia, and Epidermal growth factor receptor pathway, and enriched with Nuclear Receptor Subfamily 2 Group F Member 1 transcription factor activity. We observed an intense communication from the cancer cells to endothelial cells, mainly through the Vitronectin (VTN) to Kinase Insert Domain Receptor (KDR) pathway. A prognostic model targeting LIHC was constructed based on the disulfidoptosis-based DEGs, namely APLP2, PDIA6, YBX1, SPP1, whose accuracy was validated in multiple cohorts. Knockdown of APLP2 significantly increased the apoptosis and delayed cell cycle progression of LIHC cell line.
A prognostic model targeting LIHC was constructed based on the disulfidoptosis-related DEGs, which displayed high stability and accuracy in multiple cohorts. APLP2 played an active role in the carcinogenesis of LIHC by regulating the apoptosis and cell cycle.
作为全球第六大常见癌症，肝癌（LIHC）由于其化疗耐药性而成为严重的公共健康威胁。二硫键凋亡是一种新发现的程序性细胞死亡过程，影响正常的肌动蛋白细胞骨架结构。
从 GSE149614 和 GSE202642 数据集获取单细胞 RNA（scRNA）-seq 数据。我们利用一致流形逼近和投影聚类算法 Louvain 进行降维和 FindAllMarkers 函数确定差异表达基因（DEGs）。Monocle2 和 SCENIC 用于对选定的亚群进行伪时间序列和转录因子分析。一系列体外实验，包括集落形成实验（CFA）、针对细胞凋亡和细胞周期的流式细胞术，用于研究 APLP2 如何调节 LIHC 的进展。使用两种 LIHC 细胞系 HepG2 和 Huh7 进行 si-APLP2 转染。
通过详细的亚组分析描绘了 LIHC 的肿瘤异质性景观。我们发现 T 和 B 细胞富含 POU2F1 和 HES1 活性。炎症性癌症相关成纤维细胞通过 COL1A1/SDC1、COL1A2/SDC1 和 LUM/ITGB1 途径与癌细胞相互作用。通过细胞轨迹分析显示了正常肝细胞向恶性细胞的转化。确定为恶性细胞的 State4 富含 PI3K、缺氧和表皮生长因子受体途径，并富含核受体亚家族 2 组 F 成员 1 转录因子活性。我们观察到癌细胞与内皮细胞之间的强烈通讯，主要通过 Vitronectin (VTN) 到 Kinase Insert Domain Receptor (KDR) 途径。基于二硫键凋亡相关的 DEGs 构建了针对 LIHC 的预后模型，即 APLP2、PDIA6、YBX1、SPP1，在多个队列中验证了其准确性。APLP2 的敲低显著增加了 LIHC 细胞系的细胞凋亡并延迟了细胞周期进程。
基于二硫键凋亡相关的 DEGs 构建了针对 LIHC 的预后模型，在多个队列中表现出较高的稳定性和准确性。APLP2 通过调节细胞凋亡和细胞周期在 LIHC 的癌变中发挥积极作用。
