Olfactomedin 4 downregulation is associated with tumor initiation, growth and progression in human prostate cancer

Abstract

The olfactomedin 4 (OLFM4) gene has been analyzed as a tumor‐suppressor gene and a putative biomarker in many cancers. In our study, we analyzed the relationship of OLFM4 expression with clinicopathological features and with CpG site methylation in the OLFM4 gene promoter region in human primary prostate adenocarcinoma. OLFM4 protein expression was significantly reduced in prostate cancer tissue compared to adjacent normal tissue and was further significantly reduced in more advanced cancers. Bioinformatic studies with clinical datasets revealed that primary prostate adenocarcinoma patients with reduced OLFM4 mRNA expression exhibited higher Gleason scores and higher preoperative serum prostate‐specific antigen levels, as well as lower recurrence‐free survival. Three of the eight CpG sites in the OLFM4 gene promoter region were hypermethylated in cancerous prostate cells compared to adjacent normal cells, and reduced methylation of eight CpG sites was associated with increased OLFM4 mRNA expression in RWPE1 and PC‐3 cells. Furthermore, knockdown of OLFM4 gene expression was associated with enhanced epithelial–mesenchymal transition (EMT)‐marker expression in RWPE immortalized normal prostate cells. In contrast, restoration of OLFM4 expression in PC‐3 and DU145 prostate cancer cells lacking OLFM4 significantly inhibited both EMT‐marker expression and tumor cell growth in in vitro and in vivo models, indicating that OLFM4 may play a tumor‐suppressor role in inhibiting the EMT program, as well as tumor initiation and growth, in prostate cells. Taken together, these findings suggest that OLFM4 plays an important tumor‐suppressor role in prostate cancer progression and might be useful as a novel candidate biomarker for prostate cancer.

Olfactomedin 4 mediation of prostate stem/progenitor-like cell proliferation and differentiation via MYC

“…We have previously detected OLFM4 RNA and protein expression in RWPE1 cells 35 . RWPE1 cells are immortalized normal adult prostate epithelial cells whose growth can be maintained under serum-free conditions in 2D culture.…”

“…The OLFM4 gene plays an important role in innate immunity, inflammation, and cancers 33 . We have reported previously that OLFM4 gene expression was reduced or lost during the progression of prostate cancer due to frequent genetic deletion 34 and hypermethylation of the OLFM4 gene promoter region 35 . The expression of OLFM4 mRNA has been detected in normal prostate tissues, primary-cultured normal prostate epithelial cells, and RWPE1 immortalized normal human prostate epithelial cells 34 – 36 .…”

Genome-Wide Association Study Adjusted for Occupational and Environmental Factors for Bladder Cancer Susceptibility

“…The gliomedin paralog, olfactomedin 4, is a glycoprotein with an olfactomedin-domain, which is involved in numerous intracellular signaling pathways, including NF-κB, and is associated with innate immunity. Furthermore, olfactomedin 4 suppresses the development and progression of cancer [ 50 , 51 ], and tumorigenesis is observed in olfactomedin4 deficient mice [ 52 ]. Thus, it is hypothesized that gliomedin is also involved in the development of bladder cancer by a mechanism similar to that of olfactomedin 4 in innate immunity and oncogenesis in a certain environment.…”

Prediction of Prognosis in Patients with Prostate Cancer by DNA Methylation Classification

“…A post hoc analysis of data from a Phase 3 trial showed that the detection of serum free methylated GSTP1 (mGSTP1) DNA can predict the outcome of chemotherapy in metastatic prostate cancer and may guide treatment decisions in the clinic [26]. In addition, methylation of other genes, including olfactory 4 (OLFM4) [27], MTSS1 [7] and myeloid ecotropic viral insertion site 2 prognosis has yet to be examined in a large prostate cancer dataset. In this study, we tried to explore a classi cation method that integrates several DNA methylation markers to help clinicians evaluate the therapeutic effect and prognosis of prostate cancer patients and choose treatment strategies.…”