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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276348 | GEO | 2025/03/24

REPOSITORIES: GEO

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Project description:Background: Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology. Results: Using a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes – ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX – exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n=423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n=50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n=19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site. Conclusions: Our study identifies seven genes governed by TET2 loss in PCa which exhibit association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.

Project description:Current prostate cancer prognostic models are based on pre-treatment prostate-specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict clinical disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. We analyzed a Swedish Watchful Waiting cohort (1977â1999) with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer or developed metastases and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. We reasoned that tumor sampling might preclude the identification of the dominant metastatic nodule. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Thus the determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses preventing the development of molecular biomarkers for prostate cancer progression. 281 cases from the population-based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Training set: first 186 samples; Validation cohort: remaining 95 cases from the same population.

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

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