Exploring genes associated with metabolic dysfunction as therapeutic targets for head and neck cancers: a novel strategy

Abstract

Evidence suggests a potential link between metabolic dysfunction and head and neck cancer (HNC). This study investigates the potential causal relationships between metabolic dysfunction and HNC using genetic data. While no significant causal associations were identified between metabolic indicators and HNC risk, the research revealed that inhibition of certain genes could reduce cancer risk. Specifically, inhibiting sodium/glucose cotransporter 2 (SLC5A2) was associated with a decreased risk of HNC and oropharyngeal cancer (OPC), while ATP-sensitive inward rectifier potassium channel 11 inhibition was linked to a reduced risk of oral cavity cancer. Additionally, inhibiting SLC5A1 and voltage-dependent L-type calcium channel subunit beta-2 showed a connection to lower OPC risk. These findings suggest that targeting these genes could offer promising therapeutic strategies for preventing and treating HNC, as well as improving both preoperative and postoperative management in affected patients.

Keywords: Mendelian randomization; drug targets; head and neck cancer; metabolic dysfunction.

Figure 1.

Overview of the study design. MR, Mendelian randomization; eQTL, expression quantitative trait loci; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein–protein interaction; T2D, type 2 diabetes; CHD, coronary heart disease; SNP, single-nucleotide polymorphisms; GWAS, genome-wide association study; HNC, head and neck cancer; LC, laryngeal cancer; OCC, oral cavity cancer; OPC, oropharyngeal cancer.

Figure 2.

The main methods and operational processes of study. HbA1c, glycosylated hemoglobin; LDL-C, low-density lipoprotein; TG, triglycerides; HDL-C, high-density lipoprotein; DBP, diastolic blood pressure; SBP, systolic blood pressure; HNC, head and neck cancer; T2D, type 2 diabetes; CHD, coronary heart disease; SNP, single-nucleotide polymorphisms; GWAS, genome-wide association study.

Figure 3.

Forest plot of association of genetically proxied drug targets with risk of HNC and its subtypes. (A) Forest plot of association of genetically proxied lipid-lowering drug targets with risk of HNC and its subtypes. (B) Forest plot of association of genetically proxied hypoglycemic drug targets with risk of HNC and its subtypes. (C) Forest plot of association of genetically proxied hypertensive drug targets with risk of HNC and its subtypes. HbA1c, glycosylated hemoglobin; LDL-C, low-density lipoprotein; TG, triglycerides; HDL-C, high-density lipoprotein; DBP, diastolic blood pressure; SBP, systolic blood pressure; HNC, head and neck cancer; LC, laryngeal cancer; OCC, oral cavity cancer; OPC, oropharyngeal cancer; OR, odd ratio; HMGCR, HMG-CoA reductase; NPC1L1, Niemann–Pick C1-like protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9; APOB, Apolipoprotein B-100; ABCG5, ATP-binding cassette subfamily G member 5; ABCG8, ATP-binding cassette subfamily G member 8; LDLR, LDL receptor; LPL, lipoprotein lipase; PPARG, peroxisome proliferator-activated receptor gamma; ABCC8, ATP-binding cassette sub-family C member 8; CALCR, calcitonin receptor; DPP4, dipeptidyl peptidase 4; GIP, gastric inhibitory polypeptide; GLP1R, glucagon-like peptide 1 receptor; KCNJ11, ATP-sensitive inward rectifier potassium channel 11; PRKAB1, 5′-AMP-activated protein kinase subunit beta-1; RAMP2, receptor activity-modifying protein 2; SLC5A1, sodium/glucose cotransporter 1; SLC5A2, sodium/glucose cotransporter 2; ACE, angiotensin-converting enzyme; ADRA1A, alpha-1A adrenergic receptor; ADRA2B, alpha-2B adrenergic receptor; ADRB1, beta-1 adrenergic receptor; ADRB2, beta-2 adrenergic receptor; CACNA1C, voltage-dependent N-type calcium channel subunit alpha-1C; CACNA2D2, voltage-dependent calcium channel subunit alpha-2/delta-2; CACNB2, voltage-dependent L-type calcium channel subunit beta-2; REN, renin; SLC12A2, solute carrier family 12 member 2; SLC12A3, solute carrier family 12 member 3. Asterisk represents significance result.