The olfactory receptor OR51E2 regulates prostate cancer aggressiveness and modulates STAT3 in prostate cancer cells and in xenograft tumors
Despite significant advancements in prostate cancer detection and treatment, the molecular mechanisms driving its progression remain elusive. This study aimed to explore the role of the receptor OR51E2, which is frequently upregulated in prostate cancer, in the disease's progression. Using CRISPR-Cas9 technology, we generated monoclonal OR51E2 knockout cells to investigate the receptor's physiological effects. We assessed the tumorigenic potential of these cells both in vitro and in vivo, and conducted transcriptomic and proteomic analyses on xenograft tumors derived from the knockout cells. Additionally, we examined how varying levels of OR51E2 expression in patients from a TCGA cohort impacted disease outcomes. The OR51E2-knockout cells displayed increased proliferation, migration, adhesion, anchorage-independent colony formation, and tumor growth, leading to a more aggressive cancer phenotype. Omics analyses identified several pathways associated with significant molecular changes, particularly an aberration in the STAT3 pathway linked to IL-6 signaling, underscoring a connection to inflammatory pathways. Analysis of the TCGA cohort further revealed that prostate cancer patients with lower OR51E2 expression had worse prognoses and higher average Gleason grades compared to those with higher expression levels. This analysis also supported a role for OR51E2 in modulating the STAT3 pathway within the cohort. Overall, our findings suggest that OR51E2 plays a critical role in regulating prostate cancer progression by influencing cancer cell physiology and aggressiveness. Reduced OR51E2 expression may lead to poorer patient outcomes, potentially through disruptions in the STAT3 pathway that alter cellular responses to inflammatory signaling. Overall design: To investigate the effects of OR51E2 on in vivo prostate cancer tumor growth, we designed a stable, monoclonal OR51E2-knockout LNCaP-derived cell line. LNCaP WT or OR51E2-KO cells were injected subcutaneously in male CIEA NOG mice and were allowed to grow to a size og 1000 mm3, where the tumors were harvested and snap frozen. Total RNA was extracted from these tumors, sequenced, and the expression data was analyzed (mouse reads removed prior to analysis). 9 WT tumors and 8 KO tumors were analyzed.