Exploring the role of differentially expressed metabolic genes and their mechanisms in bone metastatic prostate cancer

Abstract

Background: Approximately 10-20% of patients diagnosed with prostate cancer (PCa) evolve into castration-resistant prostate cancer (CRPC), while nearly 90% of patients with metastatic CRPC (mCRPC) exhibit osseous metastases (BM). These BM are intimately correlated with the stability of the tumour microenvironment.

Purpose: This study aspires to uncover the metabolism-related genes and the underlying mechanisms responsible for bone metastatic prostate cancer (BMPCa).

Methods: Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets of PCa and BM were analyzed through R Studio software to identify differentially expressed genes (DEGs). The DEGs underwent functional enrichment via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), with key factors screened by a random forest utilized to establish a prognostic model for PCa. The study explored the relationship between DEGs and the stability of the immune microenvironment. The action and specificity of CRISP3 in PCa was validated through western blot analysis, CCK-8 assay, scratch assay, and cellular assay.

Results: The screening of GEO and TCGA datasets resulted in the identification of 199 co-differential genes. Three DEGs, including DES, HBB, and SLPI, were selected by random forest classification model and cox regression model. Immuno-infiltration analysis disclosed that a higher infiltration of naïve B cells and resting CD4 memory T cells occurred in the high-expression group of DES, whereas infiltration of resting M1 macrophages and NK cells was greater in the low-expression group of DES. A significant infiltration of neutrophils was observed in the high-expression group of HBB, while greater infiltration of gamma delta T cells and M1 macrophages was noted in the low-expression group of HBB. Resting dendritic cells, CD8 T cells, and resting T regulatory cells (Tregs) infiltrated significantly in the high-expression group of SLPI, while only resting mast cells infiltrated significantly in the low-expression group of SLPI. CRISP3 was established as a critical gene in BMPCa linked to DES expression. Targeting CRISP3, d-glucopyranose may impact tumour prognosis. During the mechanistic experiments, it was established that CRISP3 can advance the proliferation and metastatic potential of PCa by advancing epithelial-to-mesenchymal transition (EMT).

Conclusion: By modulating lipid metabolism and maintaining immunological and microenvironmental balance, DES, HBB, and SLPI suppress prostate cancer cell growth. The presence of DES-associated CRISP3 is a harbinger of unfavorable outcomes in prostate cancer and may escalate tumor proliferation and metastatic capabilities by inducing epithelial-mesenchymal transition.

Keywords: Bone metastasis (BM); Epithelial to mesenchymal transition (EMT); Immuno-microenvironmental homeostasis; Prostate cancer (PCa); scRNA-seq.