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Abstract
The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age ≥70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.
Highlights
Metabolic reprogramming occurs owing to various genetic, epigenetic, and post-translational aberrations in metabolic enzymes that alter signaling pathways of human cancers [1,2]
Contributing to the pro-proliferative phenotype, high hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) expression was strongly associated with HSD11B1 copy-number gain (CNG) that conferred a strong negative prognostic effect independent of the influence of high risk levels in gastrointestinal stromal tumors (GISTs)
In patients with cortisone-reductase deficiency, the mutations in HSD11B1 or hexose-6-phosphate dehydrogenase (H6PD) that encodes an enzyme furnishing cofactors for the reaction might abrogate cortisol generation and stimulate adrenal hyperandrogenism mediated by adrenocorticotropic hormone [25,26]
Summary
Metabolic reprogramming occurs owing to various genetic, epigenetic, and post-translational aberrations in metabolic enzymes that alter signaling pathways of human cancers [1,2]. We reported the amplification-driven overexpression of phospholipase C isoform β4 (PLCB4) to predict disease-free survival period through the initial reappraisal of published transcriptomic dataset for genes catalogued into the lipid metabolic bioprocess group [14]. Using this focused data-mining approach, we noted that hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) represented another top-rated and differentially upregulated gene associated with high-risk level and development of metastasis in GISTs. further genetic, transcriptional, translational, and functional characterization of HSD11B1 was performed to validate its relevance. Our results substantiate the role of HSD11B1 as a novel deregulated lipid-metabolizing enzyme that promotes GIST progression
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