High SQLE Expression and Gene Amplification Correlates with Poor Prognosis in Head and Neck Squamous Cell Carcinoma

Abstract

Objective Squalene epoxidase (SQLE) is considered a metabolic oncogene, but its biological function and prognostic value in head and neck squamous cell carcinoma (HNSCC) remain unclear. We aimed to evaluate the role of SQLE in the occurrence and development of HNSCC through bioinformatics analysis, and validation experiments. Methods Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas were used for pan-cancer analysis. SQLE expression in HNSCC was evaluated using Gene Expression Omnibus datasets and immunohistochemistry. The biological significance of SQLE in the tumor microenvironment (TME) of HNSCC was determined using TISCH, HuRI, LinkedOmics, and TIMER 2.0. The prognostic value of SQLE in HNSCC was analyzed using univariate Cox regression and Kaplan–Meier survival curves. Effect of SQLE on the Cal27 HNSCC cell line was evaluated using cell counting kit 8, wound healing, and EdU assays. Results SQLE was overexpressed and amplified in various cancers, including HNSCC. High SQLE expression promoted cell proliferation, associated with T stage in HNSCC patients. Copy number amplification and DNA demethylation contributed to high SQLE expression in HNSCC, which was associated with poor prognosis. SQLE was related to HNSCC TME, and its mRNA expression/copy number alterations were negatively correlated with the infiltration of CD8+ T cells, follicular helper T cells, and regulatory T cell infiltration and mast cell activation and positively correlated with the infiltration of M0 macrophages and resting mast cells in HNSCC. Conclusion SQLE was identified as a prognostic biomarker and a potential pharmaceutical target for HNSCC.

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

“…It has been reported that SQLE participated in the regulation of tumor development and progression. Liu et al preliminarily reported SQLE upregulation in HNSCC cells might predict poor prognosis [7]. To our knowledge, it is the first study to illustrate the functional mechanisms of SQLE in HNSCC.…”

“…Moreover, KEGG analysis showed SQLE was closely related with cell-cell interaction. Also, Liu et al illustrated SQLE expression was negatively associated with the infiltration of CD8+ T cells, follicular helper T cells, and regulatory T cell infiltration and mast cell activation in HNSCC, indicating SQLE function important role in regulating tumor microenvironment (TME) and more experimental evidence might be given [7]. Therefore, SQLE may promote the progression of HNSCC through various mechanisms, which needs to be furtherly determined in future work.…”

“…Several studies have illustrated that SQLE could promote tumor progression via synthesis of cholesterol [5,6]. Also, Liu et al preliminarily reported SQLE upregulation in HNSCC cells might predict poor prognosis [7]. However, as far as we know, the functional mechanisms of SQLE in HNSCC has not been reported.…”

Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase

“…Despite this, a specific examination of trunSM levels had not been performed in any cancer type prior to our study. We found that total SM levels were reduced in endometrial tumor tissues, which was unexpected given that high SQLE mRNA expression is a risk factor for progression of this cancer [66]. However, the reduction in total SM was accompanied by a marked increase in the proportion of the stable and constitutively active trunSM.…”

Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy

“…In colorectal cancer, SQLE is upregulated in tumor tissues compared with normal tissues, but SQLE in stages I, II, and III is higher than that in stage IV ( 22 , 23 ). Similarly, SQLE is upregulated in nasopharyngeal cancer ( 13 ), head and neck squamous cell carcinoma ( 24 ), leukemia ( 25 ), hepatocellular cancer ( 26 – 28 ), and squamous lung cancer ( 29 , 30 ).…”