microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1

• Published in: Oncogene Vol. 33; no. 40; pp. 4847 - 4856
• Main Authors: Fujiya, M, Konishi, H, Mohamed Kamel, M K, Ueno, N, Inaba, Y, Moriichi, K, Tanabe, H, Ikuta, K, Ohtake, T, Kohgo, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-10-2014; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/1504/1885/1393; 631/80/82/23; 631/80/82/39; Animals; Apoptosis; Autophagy; Binding Sites; Care and treatment; Cell Biology; Cell Line, Tumor; Colon cancer; Colonic Neoplasms - pathology; Colorectal cancer; Cytoplasm; Degradation; Gene Expression Regulation, Neoplastic; Genetic aspects; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Neoplasm Transplantation; Nucleotide sequence; Oncology; original-article; Phagosomes - metabolism; Properties; Protein Binding; Protein expression; Proteolysis; Ribonucleoproteins; RNA-binding protein; siRNA; Transfection; Xenografts; microRNAs; heterogeneous nuclear ribonucleoproteins; apoptosis; autophagy; colon cancer; ubiquitin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.429

It is well known that microRNAs (miRs) are abnormally expressed in various cancers and target the messenger RNAs (mRNAs) of cancer-associated genes. While (miRs) are abnormally expressed in various cancers, whether miRs directly target oncogenic proteins is unknown. The present study investigated the inhibitory effects of miR-18a on colon cancer progression, which was considered to be mediated through its direct binding and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). An MTT assay and xenograft model demonstrated that the transfection of miR-18a induced apoptosis in SW620 cells. A binding assay revealed direct binding between miR-18a and hnRNP A1 in the cytoplasm of SW620 cells, which inhibited the oncogenic functions of hnRNP A1. A competitor RNA, which included the complementary sequence of the region of the miR-18a-hnRNP A1 binding site, repressed the effects of miR-18a on the induction of cancer cell apoptosis.
In vitro
single and
in vivo
double isotope assays demonstrated that miR-18a induced the degradation of hnRNP A1. An immunocytochemical study of hnRNP A1 and LC3-II and the inhibition of autophagy by 3-methyladenine and ATG7, p62 and BAG3 siRNA showed that miR-18a and hnRNP A1 formed a complex that was degraded through the autophagolysosomal pathway. This is the first report showing a novel function of a miR in the autophagolysosomal degradation of an oncogenic protein resulting from the creation of a complex consisting of the miR and a RNA-binding protein, which suppressed cancer progression.