Arecoline Is Associated With Inhibition of Cuproptosis and Proliferation of Cancer-Associated Fibroblasts in Oral Squamous Cell Carcinoma: A Potential Mechanism for Tumor Metastasis

Abstract

BackgroundMetastatic disease remains the primary cause of death in patients with oral squamous cell carcinoma (OSCC), especially those who use betel nut. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are regarded as a significant component in the TME of OSCC. However, the precise mechanisms regulating CAFs in OSCC are poorly understood.MethodsThirteen genes related to the arecoline were analyzed to explore the significant ones involved in arecoline-related OSCC metastasis. The GSE139869 (n = 10) and The Cancer Genome Atlas (TCGA)-OSCC data (n = 361) were mined for the identification of the differentially expressed genes. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the independent prognostic signatures. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the functional enrichment of selected genes, and gene set enrichment analysis of cuproptosis-related genes was completed. Spearman’s analysis and Tumor Immune Estimation Resource (TIMER) were used to visualize the correlation between the infiltration of CAFs and the gene expression. The correlation analysis of the cells and different genes, including CAF infiltration and transcripts per million expression, was assessed. The relationship between arecoline and CAFs was confirmed by cell counting kit-8 assay (CCK-8). CancerSEA was searched to identify the single-cell phenotype.ResultArecoline-associated fibrosis-related OSCC differentially expressed genes (AFOC-DEGs), namely, PLAU, IL1A, SPP1, CCL11, TERT, and COL1A2, were screened out and selected from the Gene Expression Omnibus (GEO) database and TCGA database. AFOC-DEGs were highly expressed in OSCC, which led to poor survival of patients. Functional enrichment analysis, protein–protein interaction network construction, and Spearman’s correlation analysis all suggested that AFOC-DEGs were closely associated with cuproptosis. Cellular experiments demonstrated that arecoline stimulation could significantly increase the cell viability of CAFs. Single-sample Gene Set Enrichment Analysis (ssGSEA) results showed that GLS and MTF1 were highly expressed when fibroblasts proliferated at high enrichment levels. In addition, analysis of single-cell sequencing results suggested that OSCC cells with high expression of AFOC-DEGs were associated with OSCC metastasis.ConclusionWe found a close association between arecoline, cuproptosis, and CAFs, which might play an important role in the metastasis of OSCC.

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

“…Cuproptosis may function by suppressing cancer cell proliferation and inhibiting metastatic events. For instance, in patients with oral squamous cell carcinoma who take betel nut, the related arecoline stimulation may inhibit cuproptosis, significantly increasing the viability of cancer-associated fibroblasts (CAFs) [157]. CAFs is crucial in cancer progression by contributing to the promotion of the EMT, cancer metastasis and chemotherapy resistance [158,159].…”

Pyroptosis-related bioinformatics analysis reveals that IL1A is a prognostic biomarker in oral squamous cell carcinoma

“…IL1A was highly expressed in OSCC and was identi ed as an arecoline-associated brosis-related gene. According to this study, IL1A was closely associated with cuproptosis, and unsurprisingly led to the unfavorable prognosis of patients [53]. In additon, acid-electrolyzed functional water could promoted the release of IL1A in OSCC, and It was suggested that the secreted IL1A might be derived from intracellular storage sites [54].…”

Construction of a cuproptosis-associated long non-coding RNA risk prediction model for pancreatic adenocarcinoma based on the TCGA database

“…19 cuproptosis-associated genes were identified through a literature search: ATP7B, ATP7A, CDKN2A, DBT, DLD, DLAT, DLST15-19 FDX1, GCSH, GLS, LIAS, LIPT1, LIPT2, MTF1, NFE2L2, NLRP3, PDHA1, PDHB, and SLC31A1. [11,19–22] Through Pearson correlation analysis, we found that these genes were associated with 205 lncRNAs (Fig. 2).…”