Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment

Abstract

Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro . Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.

Prognostic Value of Long Noncoding RNA DLEU2 and Its Relationship with Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma

“… 12 Moreover, several studies have reported that macrophages, Tregs, and CD8+ T cells in the KIRC microenvironment can promote tumour growth and immune escape. 39–41 These results suggest that DLEU2 may influence the prognosis of KIRC and LIHC by regulating immune cell infiltration in the TME.…”

Malignant Tumor Purity Reveals the Driven and Prognostic Role of CD3E in Low-Grade Glioma Microenvironment

“…We also found that positive regulation of voltage-gated potassium channel activity is related to LGG. MicroRNAs (miRNAs) can reportedly promote the development of invasive nonfunctional pituitary adenomas (74,75). Current knowledge suggests that voltage-gated potassium channels play a fundamental role in the generation and transmission of action potential ( 76), but their role in tumors has not been deeply studied.…”

m6A Regulator-Mediated Methylation Modification Model Predicts Prognosis, Tumor Microenvironment Characterizations and Response to Immunotherapies of Clear Cell Renal Cell Carcinoma

“…Increasing studies have shown that tumor metastasis and invasion are inseparable from the microenvironment and purity of tumor cells (36). A comprehensive analysis of the role of TME in ccRCC helps to identify the tumor immunophenotype of ccRCC, explores independent prognostic indicators and novel therapeutic targets, thereby improving the prognosis of patients and the ability to predict the effect of immunotherapy (37)(38)(39). Studies have shown that tumor purity of TME is significantly related to the clinical characteristics, genome expression, and biological characteristics of tumor patients.…”