KCNN4 is a Potential Biomarker for Predicting Cancer Prognosis and an Essential Molecule that Remodels Various Components in the Tumor Microenvironment: A Pan-Cancer Study

Abstract

Objectives: Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) is a member of the KCNN family. Studies have revealed that KCNN4 is implicated in various physiological processes as well as promotes the malignant phenotypes of cancer cells. However, little is known about its associations with survival outcomes across varying cancer types.Methods: Herein, we systematically explored the prognostic value of KCNN4 in the pan-cancer dataset retrieved from multiple databases. Next, we performed correlation analysis of KCNN4 expression with tumor mutational burden (TMB) and microsatellite instability (MSI), and immune checkpoint genes (ICGs) to assess its potential as a predictor of immunotherapy efficacy. Afterwards, patients were divided into increased-risk group and decreased-risk group based on the contrasting survival outcomes in various cancer types. Furthermore, the underlying mechanisms of the distinctive effects were analyzed using ESTIMATE, CIBERSORT algorithms, and Gene Set Enrichment Analysis (GSEA) analysis.Results: KCNN4 expression levels were aberrant in transcriptomic and proteomic levels between cancer and normal control tissues in pan-cancer datasets, further survival analysis elucidated that KCNN4 expression was correlated to multiple survival data, and clinical annotations. Besides, KCNN4 expression was correlated to TMB and MSI levels in 14 types and 12 types of pan-cancers, respectively. Meanwhile, different types of cancer have specific tumor-infiltrating immune cell (TICs) profiles.Conclusions: Our results revealed that KCNN4 could be an essential biomarker for remodeling components in the tumor microenvironment (TME), and a robust indicator for predicting prognosis as well as immunotherapy response in pan-cancer patients.

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…Abnormal expression of the KCNK gene family in BC can be used as an ideal prognostic biomarker for BC patients ( 118 ). It is also a powerful indicator of pan-cancer prognosis ( 115 ). In addition, drugs related to potassium channels have gradually become the focus of current research.…”

“…Another study found that KCa3.1 activators have an inhibitory effect on IL-10 expression, and the Smad2/3 signaling pathway is involved in transcriptional inhibition of IL-10 in KCa3.1 activator-induced T-lymphoblastic leukemia HuT-78 cells, suggesting that KCa3.1 activators are a new therapeutic option that can inhibit IL-10 and evade the tumor-promoting activity of cancer immune surveillance ( 114 ). In addition, KCNN4 is significantly upregulated in many types of cancer tissues and plays an immunoregulatory role in the tumor microenvironment(TME), which is a powerful indicator of pan-cancer prognosis as well as immunotherapy ( 115 ). Extensive studies of KCa3.1 in immunotherapy have opened new avenues for treating tumors.…”

Predicting prognosis and immunotherapeutic response of clear cell renal cell carcinoma

“…It was also differentially expressed in the low and high-risk groups. KCNN4 expression was correlated to tumor mutational burden and microsatellite instability levels in 14 types and 12 types of pan-cancers (Chen et al, 2022a). KCNN4 influences tumor microenvironment by remodeling tumor-infiltrating immune cell profiles (Chen et al, 2022a).…”

“…KCNN4 expression was correlated to tumor mutational burden and microsatellite instability levels in 14 types and 12 types of pan-cancers (Chen et al, 2022a). KCNN4 influences tumor microenvironment by remodeling tumor-infiltrating immune cell profiles (Chen et al, 2022a). It may regulate immune response via raising Tregs and diminishing resting mast cells in ccRCC, which may cause the differential clinical outcomes (Cui et al, 2022).…”

The Ion Channel Gene KCNAB2 Is Associated with Poor Prognosis and Loss of Immune Infiltration in Lung Adenocarcinoma

“…Dysregulation of potassium channel genes is associated with cancer development and patient prognosis [ 12 ], and potassium channels have been proposed as potential targets for cancer therapy [ 13 , 14 ]. Previous studies have shown that silencing of potassium channel genes KCNN4 and KCND2 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma cells [ 15 , 16 , 17 ]. However, the effect of potassium channel genes on the tumor microenvironment, especially immune cell infiltration, is still poorly understood.…”