Zhao Xin, He Yichen, Pan Yi, Ye Luyi, Liu Longcai, Mou Xiaozhou, Fu Luoqin
General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Department of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Front Oncol. 2023 Feb 16;13:1044526. doi: 10.3389/fonc.2023.1044526. eCollection 2023.
The tumor microenvironment (TME) of pancreatic cancer is complex. which forms forms a microenvironment with high immunosuppression, ischemia and hypoxia, which promotes tumor proliferation and migration, inhibit the anti-tumor immune response. NOX4 plays an important role in tumor microenvironment and has a significant relationship with the occurrence, development and drug resistance of tumor.
Firstly, NOX4 expression in pancreatic cancer tissues under different pathological conditions was detected by applying immunohistochemical staining of tissue microarray (TMA). Transcriptome RNA sequencing data and clinical data of 182 pancreatic cancer samples were downloaded and collated from the UCSC xena database. 986 NOX4-related lncRNAs were filtered by Spearman correlation analysis. prognosis-related NOX4-related lncRNAs and NRlncSig Score were finally obtained by univariate and multivariate Cox regression with Least Absolute Shrinkage and Selection Operator (Lasso) analysis in pancreatic cancer patients. we plotted Kaplan -Meier and time-dependent ROC curves (ROC) to assess the validity in predicting the prognosis of pancreatic cancer. The ssGSEA analysis was applied to explore the immune microenvironment of pancreatic cancer patients as well as to discuss the immune cells and immune status separately.
We found that a mature tumor marker, NOX4, play different roles in different clinical subgroups by immunohistochemical analysis and clinical data. Finally, 2 NOX4-related lncRNAs were determined by least absolute shrinkage and selection operator (LASSO) analysis, univariate Cox analysis and multivariate COX analysis. The ROC curve and DCA curve showed that NRS Score had better predictive ability than independent prognosis-related lncRNA and other clinicopathologic indicators. We obtained the relative abundance of 28 infiltrating immune cells by ssGSEA analysis and found a significant positive correlation between the abundance of anti-tumor immune cells and tumor-promoting immune cells in the risk-classified microenvironment. No matter NRS Score or AC092667.2, RP11-349A8.3 was significantly correlated with immune infiltrating cells. Meanwhile, the IC50 of conventional chemotherapeutic agents in high-score group were significantly lower than those in low-score group.
As a mature tumor marker, NOX4-related lncRNAs provide new research strategies for prognostic evaluation, molecular mechanism and clinical treatment of pancreatic cancer.
胰腺癌的肿瘤微环境（TME）复杂，形成了具有高度免疫抑制、缺血和缺氧的微环境，促进肿瘤增殖和迁移，抑制抗肿瘤免疫反应。NOX4在肿瘤微环境中起重要作用，与肿瘤的发生、发展及耐药性密切相关。
首先，应用组织芯片（TMA）免疫组化染色检测不同病理状态下胰腺癌组织中NOX4的表达。从UCSC xena数据库下载并整理182例胰腺癌样本的转录组RNA测序数据和临床数据。通过Spearman相关分析筛选出986个与NOX4相关的lncRNA。最终通过单因素和多因素Cox回归及最小绝对收缩和选择算子（Lasso）分析，在胰腺癌患者中获得与预后相关的NOX4相关lncRNA和NRlncSig评分。绘制Kaplan-Meier曲线和时间依赖性ROC曲线（ROC）以评估预测胰腺癌预后的有效性。应用单样本基因集富集分析（ssGSEA）探讨胰腺癌患者的免疫微环境，并分别讨论免疫细胞和免疫状态。
通过免疫组化分析和临床数据发现，成熟的肿瘤标志物NOX4在不同临床亚组中发挥不同作用。最终，通过最小绝对收缩和选择算子（LASSO）分析、单因素Cox分析和多因素COX分析确定了2个与NOX4相关的lncRNA。ROC曲线和决策曲线分析（DCA）曲线显示，NRS评分比独立的预后相关lncRNA和其他临床病理指标具有更好的预测能力。通过ssGSEA分析获得了28种浸润免疫细胞的相对丰度，发现在风险分类微环境中抗肿瘤免疫细胞和促肿瘤免疫细胞的丰度之间存在显著正相关。无论NRS评分还是AC092667.2、RP11-349A8.3均与免疫浸润细胞显著相关。同时，高分组中传统化疗药物的半数抑制浓度（IC50）显著低于低分组。
作为一种成熟的肿瘤标志物，与NOX4相关的lncRNA为胰腺癌的预后评估、分子机制及临床治疗提供了新的研究策略。
