Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Abstract

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.

Insights into Human Epileptogenesis with Proteomic Profiling

“…This regulation may influence interactions with the extracellular environment and substrate associations. While PPFIA4’s role has been observed predominantly in various cancer contexts, there’s been little exploration of its relation to epilepsy, barring a case report involving drug-resistant focal onset epilepsy in connection with PPFIA4 gene variants(Sourbron et al, 2021; Xie et al, 2020; Xu et al, 2022; Zhao et al, 2022; Zhou et al, 2022).…”

Functional Gene Signature Offers a Powerful Tool for Characterizing Clinicopathological Features and Depicting Tumor Immune Microenvironment of Colorectal Cancer

“…HALLMARK_HYPOXIA: This gene signature contained 200 genes and could be searched in GSEA database (http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_HYPOXIA.html) [11]. It has been identi ed to be related to the clinicopathological features and immune status of colorectal cancer in our previous studies [12,13].…”

Predictive biomarkers of colon cancer immunotherapy: Present and future

“…The CPM score has the potential of discriminating mCRC patients who exhibited clinical benefits from pembrolizumab ( 124 ). Additionally, using multiplex immunohistochemistry (mIHC), multiple immune indicators combined with PD-L1 expression can be analyzed simultaneously as well as report TME in various solid tumors, including colon cancer ( 28 , 141 , 142 ).…”

“…Transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors showed that hypoxia-related signaling pathways were upregulated in ICI nonresponders ( 76 ). Recently, several studies proposed that hypoxia-related genes can be classified as predicting immune cell infiltration and prognosis of colon cancer patients ( 25 , 28 , 150 ). These genes provide potential therapeutic targets for immunotherapy as well as prognostic biomarkers for colon cancer patients.…”

“…New techniques, such as multiplex immunohistochemistry (mIHC) and single-cell RNA sequencing, could provide a more comprehensive evaluation of the TME and genetic heterogeneity in colon cancer. This will help find precise biomarkers for screening and efficacy assessment of colon cancer immunotherapy beneficiary populations ( 28 , 29 ). In this review, we comprehensively summarize the reported biomarkers of colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.…”