Wang Yao, Zhu Xiao Fei, Gu Wan Jian, Zhang Gui Hong
Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155, Han'Zhong Road, Qinhuai, Nanjing, 210029, Jiangsu, China.
Discov Oncol. 2025 Mar 25;16(1):393. doi: 10.1007/s12672-025-02164-4.
The unfolded protein response (UPR) is an adaptive and cytoprotective sensing-signaling network. Numerous studies have indicated the crucial role of UPR in the anti-tumor drug resistance and the modification of tumor microenvironment (TME). The aim of this study is to analyze the alterations of microenvironment and key regulatory genes in hepatocellular carcinoma (HCC) with high UPR activity.
We profiled differentially expressed genes (DEGs) by UPR activity, and the biological functions of DEGs and the alterations of signaling pathways were explored. The Immune/Stromal scores and relative abundance of infiltrating cells of HCC tissues with RNA sequencing data downloaded from The Cancer Genome Atlas (TCGA) were calculated by the xCell and ESTIMATE algorithm. The correlations between the prognostic UPR-related genes with the microenvironment scores and infiltrating cells were analyzed using R package "corrplot".
Our results demonstrated that UPR-related genes mainly involved in immune-related signaling pathways. Microenvironment analysis revealed that HCC tissues with higher UPR activity had lower Stromal scores and the relative abundance of various infiltrating cells including hematopoietic stem cells (HSC), lymphatic endothelial cells (LECs), microvascular endothelial cells, endothelial cells (ECs) and adipocytes decreased most significantly. Kaplan-Meier survival analysis indicated that the decline of Stromal scores and corresponding infiltrating stromal cells would result in worse prognosis. The expression levels of CLEC3B, RAMP3, GPR182 and DNASE1L3 were significantly positively correlated with Stromal scores and various infiltrating stromal cells, and down-regulation of these genes were also associated with worse prognosis of HCC.
HCC with high UPR activity had lower Stromal scores and worse prognosis. Down-regulated genes CLEC3B, RAMP3, GPR182 and DNASE1L3 may play an important regulatory role in the modification of microenvironment of HCC with high UPR activity.
未折叠蛋白反应（UPR）是一种适应性和细胞保护的传感信号网络。大量研究表明UPR在抗肿瘤耐药性及肿瘤微环境（TME）重塑中起关键作用。本研究旨在分析具有高UPR活性的肝细胞癌（HCC）中微环境及关键调控基因的变化。
我们根据UPR活性对差异表达基因（DEG）进行了分析，并探究了DEG的生物学功能及信号通路的变化。通过xCell和ESTIMATE算法，利用从癌症基因组图谱（TCGA）下载的RNA测序数据计算HCC组织的免疫/基质评分及浸润细胞的相对丰度。使用R包“corrplot”分析与预后相关的UPR基因与微环境评分及浸润细胞之间的相关性。
我们的结果表明，与UPR相关的基因主要参与免疫相关信号通路。微环境分析显示，具有较高UPR活性的HCC组织的基质评分较低，包括造血干细胞（HSC）、淋巴管内皮细胞（LEC）、微血管内皮细胞、内皮细胞（EC）和脂肪细胞在内的各种浸润细胞的相对丰度下降最为显著。Kaplan-Meier生存分析表明，基质评分及相应浸润性基质细胞的下降会导致预后更差。CLEC3B、RAMP3、GPR182和DNASE1L3的表达水平与基质评分及各种浸润性基质细胞显著正相关，这些基因的下调也与HCC的预后较差有关。
具有高UPR活性的HCC基质评分较低，预后较差。下调基因CLEC3B、RAMP3、GPR182和DNASE1L3可能在具有高UPR活性的HCC微环境重塑中起重要调节作用。
