microRNA Determinants of Neuroendocrine Differentiation in Prostate Cancer
Abstract
Since the last report on Dec 31, 2022, we made significant progress on deciphering the role of microRNAs in driving neuroendocrine differentiation in advanced prostate cancer.We demonstrated that progression of advanced CRPC with adenocarcinoma characteristics (CRPC-Adeno) to therapy-induced, androgen-independent NE (CRPC-NE) states is associated with a characteristic set of miRNA alterations that promote neuroendocrine differentiation in advanced prostate cancer. Our data support that in addition to key genomic alterations that drive neuroendocrine prostate cancer, characteristic miRNA alterations are needed that promote epithelial-to-mesenchymal transition and other cellular processes that drive lineage switching.Importantly, we developed and validated a novel miRNA classifier to stratify CRPC-NE tumors from CRPCA deno carcinomas. Our studies suggest that using a minimal set of 5- miRNA genes, CRPC-Adenocarcinomas can be distinguished from CRPC-NE tumors. These miRNA alterations included miR-10a-5p, miR-28-3p, miR-181-3p,miR-92b-3p and miR-375. We examined the potential regulation of neuronal genes by these miRNAs and found a significant correlation between miRNA expression and expression of neuronal markers SYP, ENO2 and CHGA.This classifier included downregulation of miR-28-3p as an important feature. Therefore, we examined the functional role of miR-28-3p in prostate cancer in more detail. Our in vitro and in vivo studies on miR-28-3psupport a tumor suppressive role of this miRNA in advanced prostate cancer. Further, we validated Vimentin as a target for miR-28-3p. In view of these data, we propose that loss of expression of miR-28-3p in advanced prostate cancer leads to the upregulation of Vimentin and induction of epithelial-to-mesenchymal transition (EMT), favoring tumor progression. We continued our studies on miR-410, a proposed miRNA in the proposal. Our studies show thatmiR-410 plays a context dependent role in prostate cancer. We found that this
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1217480
Entities
People
- Saini Sharanjot
Organizations
- Augusta University