406952

MIR17

The purpose of this study is to identify metastasis-associated genes/signaling pathways in basal-like breast tumors. Kaplan-Meier analysis of two public meta-datasets and functional classification was used to identify genes/signaling pathways significantly associated with distant metastasis free survival. Integrated analysis of expression correlation and interaction between mRNAs and miRNAs was used to identify miRNAs that potentially regulate the expression of metastasis-associated genes. The novel metastatic suppressive role of miR-17-5p was examined by in vitro and in vivo experiments. Over 4,000 genes previously linked to breast tumor progression were examined, leading to identification of 61 and 69 genes significantly associated with shorter and longer DMFS intervals of patients with basal-like tumors, respectively. Functional annotation linked most of the pro-metastatic genes to epithelial mesenchymal transition (EMT) process and three intertwining EMT-driving pathways (hypoxia, TGFB and Wnt), whereas most of the anti-metastatic genes to interferon signaling pathway. Members of three miRNA families (i.e., miR-17, miR-200 and miR-96) were identified as potential regulators of the pro-metastatic genes. The novel anti-metastatic function of miR-17-5p was confirmed by in vitro and in vivo experiments. We demonstrated that miR-17-5p inhibition in breast cancer cells enhanced expression of multiple pro-metastatic genes, rendered cells metastatic properties, and accelerated lung metastasis from orthotopic xenografts. In contrast, intratumoral administration of miR-17-5p mimic significantly reduced lung metastasis. These results provide evidence supporting that EMT activation and IFN pathway inactivation are markers of metastatic progression of basal-like tumors, and members of miR-17, miR-200, and miR-96 families play a role in suppressing EMT and metastasis. The metastasis-associated genes identified in this study have potential prognostic values and functional implications, thus, can be exploited as therapeutic targets to prevent metastasis of basal-like breast tumors.

MicroRNA-17 (miRNA-17/miR17) expression has been confirmed to be significantly higher in colorectal cancer tissues than in normal tissues. However, its exact role in colorectal cancer has not yet been fully elucidated. In this study, we found that miR-17 not only promoted epithelial-mesenchymal transition (EMT), but also promoted the formation of a stem cell-like population in colon cancer DLD1 cells. We also wished to determine the role of cytochrome P450, family 7, subfamily B, polypeptide 1 (CYP7B1) in CRC. miR-17 was overexpressed using a recombinant plasmid and CYP7B1 was silenced by transfection with shRNA. Western blot analysis was used to determine protein expression in the DLD1 cells and in tumor tissues obtained from patients with colon cancer. Our results revealed that miR17 overexpression led to the degradation of CYP7B1 mRNA expression in DLD1 cells. In addition, we found that the silencing of CYB7B1 promoted EMT and the formation of a stem cell-like population in the cells. Thus, our findings demonstrate that miR17 induces EMT consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.

MicroRNAs (miRNAs), a novel class of important gene-regulatory molecules, correlates with tumor growth, invasion, metastasis, and chemo resistance in gastric cancer (GC). Microarray analysis revealed that aberrant expressed microRNA-17 (miR-17) and DEDD were identified in GC. DEDD has been found to act as an endogenous suppressor of tumor growth and metastasis through epithelial-mesenchymal transition (EMT) process. However, the role of miRNA-17 (miR-17) has not been clearly evaluated in GC, thereby a series of in vitro experiments were performed in this study. The levels of miR-17 and DEDD in GC tissues from patients diagnosed with GC and in five GC cell lines (SGC-7901, MKN-45, HGC-27, BGC823, and AGS) were detected. It was found that miR-17 up-regulated and DEDD down-regulated in GC, and SGC-7901 and AGS cells were adopted for the in vitro cell experiments, in which the expression of miR-17 or DEDD was regulated by transfection. DEDD was validated to be a target gene of miR-17. Inhibition of miR-17 impaired EMT in GC cells. In addition, transwell assay and scratch test results revealed that inhibition of miR-17 hindered GC cell invasion and migration. Moreover, inhibition of miR-17 reduced resistance to cisplatin- or 5-Fu in GC cells and induced cisplatin- or 5-Fu-treated GC cell apoptosis, which evaluated by using CCK-8 and flow cytometry assays. From the short review above, the key findings emerge that inhibition of miR-17 may have tumor suppressive effects on GC and enhance its chemosensitivity by promoting DEDD, highlighting a novel target for GC therapy.CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved.