MicroRNA-17-3p is a prostate tumor suppressor in vitro and in vivo, and is decreased in high grade prostate tumors analyzed by laser capture microdissection

Abstract

MicroRNAs (miRs) are a novel class of RNAs with important roles in regulating gene expression. To identify miRs controlling prostate tumor progression, we utilized unique human prostate sublines derived from the parental P69 cell line, which differ in their tumorigenic properties in vivo. Grown embedded in laminin-rich extracellular matrix (lrECM) gels these genetically-related sublines displayed drastically different morphologies correlating with their behaviour in vivo. The non-tumorigenic P69 subline grew as multicellular acini with a defined lumen and basal/polar expression of relevant marker proteins. M12, a highly tumorigenic, metastatic derivative, grew as a disorganized mass of cells with no polarization, whereas the F6 subline, a weakly tumorigenic, non-metastatic M12 variant, reverted to acini formation akin to the P69 cell line. These sublines also differed in expression of vimentin, which was high in M12, but low in F6 and P69 sublines. Analysis of vimentin's conserved 3'-UTR suggested several miRs that could regulate vimentin expression. The lack of miR-17-3p expression correlated with an increase in vimentin synthesis and tumorigenicity. Stable expression of miR-17-3p in the M12 subline reduced vimentin levels 85% and reverted growth to organized, polarized acini in lrECM gels. In vitro motility and invasion assays suggested a decrease in tumorigenic behaviour, confirmed by reduced tumor growth in male athymic, nude mice dependent on miR-17-3p expression. Analysis of LCM-purified clinical human prostatectomy specimens confirmed that miR-17-3p levels were reduced in tumor cells. These results suggest that miR-17-3p functions as a tumor suppressor, representing a novel target to block prostate tumor progression.

MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop

“…In support of this hypothesis, mir-30e and miR-30e* produced from one pre-miRNA have been shown to target two sets of entirely different genes (33). Zhang et al found miR-30e and miR-30e* to be significantly upregulated in the brain of B6C3F1 mice fed diets supplemented with hexahydro-1,3,5-trinitro-1,3,5 -triazine (RDX), a potential human carcinogen, causing neurotoxicity, immunotoxicity, and an increased likelihood of cancer development (35). Thus, it would be of great interest to further determine whether targeting the whole stem loop of the miR-30e/30e* pre-miRNA can be a potential strategy for inhibition of multiple aggressive features of gliomas.…”

“…miRNAs have been demonstrated to play important roles in the initiation and progression of human cancers and therefore may represent promising targets for anticancer therapies (27)(28)(29)(30)(31)(32). During the miRNA maturation process, two functional complementary short RNA molecules, designated miRNA and miRNA*, are formed (33)(34)(35)(36). Here, using the human glioma as a model, we report a miRNA*-mediated mechanism that disrupts the NF-κB/IκB negative feedback loop and results in constitutive activation of NF-κB, leading to the aggressiveness of glioma.…”

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

“…Interestingly, Takeshita et al 46 reported that systemic delivery of miR-16 by atelocollagen inhibits the growth of metastatic prostate cancer in bone of nude mice, and may potentially be used for the treatment of metastatic prostate cancer. Zhang et al 47 observed that miR-17-3p regulates the expression of vimentin and altered expression of miR-17-3p decreases the tumorigenic behavior and reduces tumor size in nude mice. Saini et al 51 also noted that relative miR-203 expression is lower in prostate cancer cell lines derived from bone metastasis, and over-expression of miR-203 has a negative effect on the development of metastases in nude mice.…”

The effects of perfluorocarbon on ICAM-1 expression in LPS-induced A549 cells and the potential mechanism

“…miR-17-3p has 22 nucleotides, and there are several studies about its functions (45). A study by Suárez et al (30) has shown that ICAM-1 is a target of TNF-induced miR-17-3p in endothelial cells.…”