Xu Yixin, Cao Can, Zhu Ziyan, Wang Yibo, Tan Yulin, Xu Xuezhong
Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.
Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China.
Front Genet. 2022 Jun 6;13:901734. doi: 10.3389/fgene.2022.901734. eCollection 2022.
Hypoxia, a typical hallmark of numerous tumors, indicates poor infiltration of antitumor lymphocytes, as well as facilitates the development, progression, and drug resistance of malignant cells. Here, the present research was performed to identify novel hypoxia-related molecular markers and their correlation to the tumor immune microenvironment (TIME) in colon cancer. The expression of hypoxia-related gene signature was extracted from The Cancer Genome Atlas (TCGA) COAD cohort. Based on this signature, a risk score model was constructed using the Lasso regression model. Its discrimination ability and stability were validated in another independent cohort (GSE17536) from Gene Expression Omnibus (GEO) database. Moreover, molecular biology experiments (quantitative real-time PCR and multiple immunohistochemistry) were performed to validate the results of bioinformatics analyses. Three hub genes, including PPFIA4, SERPINE1, and STC2, were chosen to build the risk score model. All of these genes were increasingly expressed in the hypoxia subgroup (HS). Compared with the normoxia subgroup (NS), HS had worse pathological features (T, N, M, and stage) and overall survival (OS), more expression of immune checkpoint molecules, poorer infiltration of some pro-inflammation immune cells (CD4 T cells and CD8 T cells), and enriched infiltration of M0/M2 macrophages. After the risk model was proven to be valuable and stable, a nomogram was built based on this model and some clinicopathological factors. Moreover, it had been identified that three hub genes were all increasingly expressed in hypoxic conditions by quantitative real-time PCR (qPCR). The results of multiple immunohistochemistry (mIHC) also showed that higher expression of hub genes was associated with poorer infiltration of pro-inflammation immune cells (CD8 T cells and M1 macrophages) and richer infiltration of anti-inflammation immune cells (Treg cells and M2 macrophages). In conclusion, the present study uncovered the relations among hypoxia, TIME, and clinicopathological features of colon cancer. It might provide new insight and a potential therapeutic target for immunotherapy.
缺氧是众多肿瘤的典型特征，它表明抗肿瘤淋巴细胞浸润不良，同时促进恶性细胞的发展、进展和耐药性。在此，本研究旨在鉴定结肠癌中与缺氧相关的新型分子标志物及其与肿瘤免疫微环境（TIME）的相关性。从癌症基因组图谱（TCGA）结肠癌队列中提取缺氧相关基因特征的表达。基于该特征，使用套索回归模型构建风险评分模型。其判别能力和稳定性在来自基因表达综合数据库（GEO）的另一个独立队列（GSE17536）中得到验证。此外，进行了分子生物学实验（定量实时PCR和多重免疫组织化学）以验证生物信息学分析的结果。选择包括PPFIA4、SERPINE1和STC2在内的三个枢纽基因构建风险评分模型。所有这些基因在缺氧亚组（HS）中表达均增加。与常氧亚组（NS）相比，HS具有更差的病理特征（T、N、M和分期）和总生存期（OS），免疫检查点分子表达更多，一些促炎免疫细胞（CD4 T细胞和CD8 T细胞）浸润较差，以及M0/M2巨噬细胞浸润增加。在风险模型被证明有价值且稳定后，基于该模型和一些临床病理因素构建了列线图。此外，通过定量实时PCR（qPCR）已确定三个枢纽基因在缺氧条件下均表达增加。多重免疫组织化学（mIHC）结果还表明，枢纽基因的高表达与促炎免疫细胞（CD8 T细胞和M1巨噬细胞）浸润较差和抗炎免疫细胞（调节性T细胞和M2巨噬细胞）浸润较多相关。总之，本研究揭示了结肠癌缺氧、TIME和临床病理特征之间的关系。它可能为免疫治疗提供新的见解和潜在的治疗靶点。
