Department of General Surgery, Wuxi Fifth People's Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu, China.
Department of General Surgery, No.971 Hospital of PLA Navy, Qingdao, China.
BMC Med Genomics. 2024 Jan 2;17(1):2. doi: 10.1186/s12920-023-01781-8.
Lymphangiogenesis plays an important role in tumor progression and is significantly associated with tumor immune infiltration. However, the role and mechanisms of lymphangiogenesis in colorectal cancer (CRC) are still unknown. Thus, the objective is to identify the lymphangiogenesis-related genes associated with immune infiltration and investigation of their prognosis value.
mRNA expression profiles and corresponding clinical information of CRC samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The lymphangiogenesis-related genes (LymRGs) were collected from the Molecular Signatures database (MSigDB). Lymphangiogenesis score (LymScore) and immune cell infiltrating levels were quantified using ssGSEA. LymScore) and immune cell infiltrating levels-related hub genes were identified using weighted gene co-expression network analysis (WGCNA). Univariate Cox and LASSO regression analyses were performed to identify the prognostic gene signature and construct a risk model. Furthermore, a predictive nomogram was constructed based on the independent risk factor generated from a multivariate Cox model.
A total of 1076 LymScore and immune cell infiltrating levels-related hub genes from three key modules were identified by WGCNA. Lymscore is positively associated with natural killer cells as well as regulator T cells infiltrating. These modular genes were enriched in extracellular matrix and structure, collagen fibril organization, cell-substrate adhesion, etc. NUMBL, TSPAN11, PHF21A, PDGFRA, ZNF385A, and RIMKLB were eventually identified as the prognostic gene signature in CRC. And patients were divided into high-risk and low-risk groups based on the median risk score, the patients in the high-risk group indicated poor survival and were predisposed to metastasis and advanced stages. NUMBL and PHF21A were upregulated but PDGFRA was downregulated in tumor samples compared with normal samples in the Human Protein Atlas (HPA) database.
Our finding highlights the critical role of lymphangiogenesis in CRC progression and metastasis and provides a novel gene signature for CRC and novel therapeutic strategies for anti-lymphangiogenic therapies in CRC.
淋巴管生成在肿瘤进展中起着重要作用，与肿瘤免疫浸润显著相关。然而，淋巴管生成在结直肠癌（CRC）中的作用和机制尚不清楚。因此，本研究旨在确定与免疫浸润相关的淋巴管生成相关基因，并探讨其预后价值。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）数据库中获取结直肠癌样本的 mRNA 表达谱和相应的临床信息。从分子特征数据库（MSigDB）中收集淋巴管生成相关基因（LymRGs）。使用 ssGSEA 量化淋巴管生成评分（LymScore）和免疫细胞浸润水平。使用加权基因共表达网络分析（WGCNA）确定 LymScore）和免疫细胞浸润水平相关的枢纽基因。进行单因素 Cox 和 LASSO 回归分析，以确定预后基因特征并构建风险模型。此外，基于多因素 Cox 模型生成的独立风险因素构建预测列线图。
通过 WGCNA 共鉴定出与 3 个关键模块的 LymScore 和免疫细胞浸润水平相关的 1076 个枢纽基因。Lymscore 与自然杀伤细胞以及调节性 T 细胞浸润呈正相关。这些模块基因富集在细胞外基质和结构、胶原纤维组织、细胞-基质粘附等方面。最终确定 NUMBL、TSPAN11、PHF21A、PDGFRA、ZNF385A 和 RIMKLB 为 CRC 的预后基因特征。并根据中位风险评分将患者分为高风险和低风险组，高风险组患者的生存较差，易发生转移和晚期。与正常样本相比，在人类蛋白质图谱（HPA）数据库中，肿瘤样本中 NUMBL 和 PHF21A 上调，但 PDGFRA 下调。
本研究结果强调了淋巴管生成在 CRC 进展和转移中的关键作用，并为 CRC 提供了一个新的基因特征和新的抗淋巴管生成治疗策略。
