Upregulated miR-155 in papillary thyroid carcinoma promotes tumor growth by targeting APC and activating Wnt/β-catenin signaling

Abstract

Context: MicroRNAs (miRNAs) are strongly implicated in many cancers, including papillary thyroid carcinoma (PTC), which is the most common malignancy in thyroid tissue. Recently, miRNA-155 (miR-155) has been proved to play a substantial role in liposarcoma and breast cancer, but its functions in the context of PTC remain unknown. Objectives: The objective was to investigate the potential involvement of miR-155 in PTC. Design: Expression levels of miR-155 were assessed via quantitative real-time PCR in 20 pairs of human PTC and adjacent normal tissues and in 4 human PTC cell lines. Lentiviral miR-155 over expression models were performed in TPC-1 and CGTH-W3 cells, and the effects on cell growth were evaluated. We have searched for miR-155 targets and identified the hypothesis that miR-155 could promote tumor growth of PTC by targeted regulation of adenomatous polyposis coli (APC) expression and activating the Wnt/β-catenin signaling. Results: MiR-155 levels were markedly increased in PTC specimens and PTC cell lines. Over expression of miR-155 dramatically promoted PTC cell viability and colony formation in vitro, whereas miR-155 depletion reduced these parameters. Further studies revealed that APC is a novel miR-155 target, because miR-155 bound directly to its 3β-untranslated region and reduced both the mRNA and protein levels of APC. Similar to the miR-155 over-expression, APC down regulation promoted cell growth, whereas rescued APC expression reversed the promotive effect of miR-155. Furthermore, miR-155 over expression resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclin D1, TCF-1. and LEF-1. Depletion of β-catenin partially prevented miR-155-induced tumor cell viability and colony formation. In xenograft animal experiments, we found over expressed miR-155 effectively promoted tumor growth of PTC cells. Conclusions: Our results indicate that miR-155 functions asanoncogenein PTC. By targeting APC, miR-155 efficiently regulates the Wnt/β-catenin signaling.AndmiR-155 may be a potential therapeutic or diagnostic/ prognostic target for treating PTC. Copyright © 2013 by The Endocrine Society.