The olfactory receptor OR51E2 regulates prostate cancer aggressiveness and modulates STAT3 in prostate cancer cells and in xenograft tumors.

Abstract

Background: Despite advancements in the detection and treatment of prostate cancer, the molecular mechanisms underlying its progression remain unclear. This study aimed to investigate the role of the receptor OR51E2, which is commonly upregulated in prostate cancer, in the progression of this disease.

Methods: We investigated the physiological effects of OR51E2 through CRISPR-Cas9-induced monoclonal OR51E2 knockout. We assessed in vitro and in vivo tumorigenicity and conducted transcriptomic and proteomic analyses of xenograft tumors derived from these knockout cells. Furthermore, we analyzed the effects of differences in OR51E2-expression levels in patients from a TCGA cohort.

Results: OR51E2-knockout cells exhibited increased proliferation, migration, adhesion, anchorage-independent colony formation, and tumor growth rates, resulting in a more aggressive cancer phenotype. Omics analyses revealed several potential pathways associated with significant molecular changes, notably an aberration in the STAT3 pathway linked to IL-6 signaling, highlighting a connection to inflammatory pathways. TCGA cohort analysis revealed that prostate cancer patients with low tumor OR51E2 expression had a worse prognosis and a higher average Gleason grade than those with higher expression levels. Additionally, this analysis supported the putative OR51E2-related modulation of the STAT3 pathway.

Conclusions: OR51E2 is regulated throughout prostate cancer progression and actively influences cancer cell physiology affecting cancer aggressiveness. Reduced OR51E2 expression may adversely affect patient outcomes, potentially through alterations in the STAT3 pathway that impact cellular responses to inflammatory signaling.