MAPK and JAK/STAT pathways targeted by miR-23a and miR-23b in prostate cancer: computational and in vitro approaches

Abstract

The long-lasting inadequacy of existing treatments for prostate cancer has led to increasing efforts for developing novel therapies for this disease. MicroRNAs (miRNAs) are believed to have considerable therapeutic potential due to their role in regulating gene expression and cellular pathways. Identifying miRNAs that efficiently target genes and pathways is a key step in using these molecules for therapeutic purposes. Moreover, computational methods have been devised to help identify candidate miRNAs for each gene/pathway. MAPK and JAK/STAT pathways are known to have essential roles in cell proliferation and neoplastic transformation in different cancers including prostate cancer. Herein, we tried to identify miRNAs that target these pathways in the context of prostate cancer as therapeutic molecules. Genes involved in these pathways were analyzed with various algorithms to identify potentially targeting miRNAs. miR-23a and miR-23b were then selected as the best potential candidates that target a higher number of genes in these pathways with greater predictive scores. We then analyzed the expression of candidate miRNAs in LNCAP and PC3 cell lines as well as prostate cancer clinical samples. miR-23a and miR-23b showed a significant downregulation in cell line and tissue samples, a finding which is consistent with overactivation of these pathways in prostate cancer. In addition, we overexpressed miR-23a and miR-23b in LNCAP and PC3 cell lines, and these two miRNAs decreased IL-6R expression which has a critical role in these pathways. These results suggest the probability of utilizing miR-23a and miR-23b as therapeutic targets for the treatment of prostate cancer.

MicroRNA‐23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway

“…In addition, previous studies proved that the MAPK/ERK signaling pathway exerted key roles in the tumorigenesis, tumor invasiveness, as well as drug resistance of a wide range of tumors . As previously reported, the MAPK pathway could be targeted by miR‐23a and miR‐23b in prostate cancer . Interestingly, our findings demonstrated that miR‐23a mimic and siRNA‐SDCBP down‐regulated mRNA and protein levels Bcl‐2, Vim, PCNA, ERK and MAPK, as well as reduced protein level of p‐ERK and p‐MAPK.…”

“…Recent studies on the MAPK/ ERK signaling pathway revealed its tumorigenesis effect in a wide range of tumors, including accelerating cell proliferation, facilitating tumor invasiveness, and developing drug resistance to chemo agents (24)(25)(26). Previously, the MAPK pathway was reported to be targeted by miR-23a and miR-23b in prostate cancer (27). However, to the best of our knowledge, the specific effect of miR-23a and SDCBP on melanoma through the MAPK/ ERK signaling pathway still remains unclear.…”

Mir-23A Acts as An Oncogene in Pancreatic Carcinoma by Targeting Foxp2

“…On the contrary, He et al 26 reported miR-23a was lowly expressed in osteosarcoma cells and tissues compared with normal controls. miR-23a also showed a significant downregulation in prostate cancer cell line and tissue samples 27. This implies that the regulatory role of miR-23a may be specific to tumor context.…”

Effects of MicroRNA-23a on Differentiation and Gene Expression Profiles in 3T3-L1 Adipocytes

“…This implies that the Jak-Stat signaling pathway transduces the effects of miR-23a in adipocytes. Similarly, a recent paper also reported miR-23 targets Jak-Stat pathways in prostate cancer through computational and in vitro studies [36]. …”