Journal Article

microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis

Wang, H, Chen, M, Chen, J, Cai, M, Yu, J, Ng, S S M, Li, X, Wu, C W, Sung, J J Y, Zhang, N, Mok, M T S, Dong, Y

2013

Overview

Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation ( P <0.05), induced apoptosis ( P <0.05) and caused cell-cycle arrest in G1 phase ( P <0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice ( P <0.05). The 3′-untranslated region (3′UTR) of Yin Yang 1 ( YY1 ) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3′UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation ( P <0.01) and induced apoptosis ( P <0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation ( P <0.01) and suppressing apoptosis ( P <0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model ( P <0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating β-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan–Meier survival curves showed that these patients had significantly shorter survival than others ( P <0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1 . YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 3' Untranslated Regions / 631/67/395 / 692/420/755 / 692/699/67/1504/1885 / Animals / Apoptosis / Apoptosis - genetics / beta Catenin - metabolism / Binding sites / Biomarkers, Tumor / c-Jun protein / Carcinogenesis / Caspase / Cell Biology / Cell growth / Cell Line, Tumor / Cell Proliferation / Cellular signal transduction / Colon cancer / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - mortality / Colorectal Neoplasms - pathology / Ectopic expression / Female / Fibroblast growth factor 4 / G1 phase / G1 Phase Cell Cycle Checkpoints - genetics / Gene expression / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Genes, p53 / Genetic aspects / HCT116 Cells / Human Genetics / Humans / Internal Medicine / Kaplan-Meier Estimate / Male / Medicine / Medicine & Public Health / Mice, Nude / MicroRNA / MicroRNAs / MicroRNAs - genetics / Middle Aged / miRNA / mRNA / Multivariate analysis / Observations / Oncology / original-article / p53 Protein / Prognosis / Properties / Signal transduction / Survivin / Transcription factors / Tumor cell lines / Tumorigenesis / Wnt protein / Wnt Signaling Pathway / Xenograft Model Antitumor Assays / Xenografts / YY1 protein / YY1 Transcription Factor - genetics / YY1 Transcription Factor - metabolism / β-Catenin