MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Abstract

Hepatoblastoma (HBL) is the most common pediatric liver cancer. In this malignant neoplasm, beta‐catenin protein accumulates and increases Wnt signaling due to recurrent activating mutations in the catenin‐beta 1 (CTNNB1) gene. Therefore, beta‐catenin is a key therapeutic target in HBL. However, controlling beta‐catenin production with therapeutic molecules has been challenging. New biological studies could provide alternative therapeutic solutions for the treatment of HBL, especially for advanced tumors and metastatic disease. In this study, we identified microRNAs (miRNAs) that target beta‐catenin and block HBL cell proliferation in vitro and tumor growth in vivo. Using our dual‐fluorescence‐FunREG system, we screened a library of 1,712 miRNA mimics and selected candidates inhibiting CTNNB1 expression through interaction with its untranslated regions. After validating the regulatory effect of nine miRNAs on beta‐catenin in HBL cells, we measured their expression in patient samples. Let‐7i‐3p, miR‐449b‐3p, miR‐624‐5p, and miR‐885‐5p were decreased in tumors compared to normal livers. Moreover, they inhibited HBL cell growth and Wnt signaling activity in vitro partly through beta‐catenin down‐regulation. Additionally, miR‐624‐5p induced cell senescence in vitro, blocked experimental HBL growth in vivo, and directly targeted the beta‐catenin 3′‐untranslated region. Conclusion: Our results shed light on how beta‐catenin‐regulating miRNAs control HBL progression through Wnt signaling inactivation. In particular, miR‐624‐5p may constitute a promising candidate for miRNA replacement therapy for HBL patients. (Hepatology Communications 2017;1:168‐183)

New insights into diagnosis and therapeutic options for proliferative hepatoblastoma

“…Statistical analyses were performed using GraphPad Prism 6.0 software as described. (17) See Supporting Information for further methods.…”

“…All patients were recruited in accordance with European and French law and institutional ethical guidelines . A set of 73 liver samples (44 HB and 29 nontumoral [NT] liver including 29 pairs of tumor and adjacent NT liver) was collected from 39 patients treated at French university hospitals or from the SIOPEL Liver Tumor and Tissue Bank (http://www.siopel.org).…”

“…All patients were recruited in accordance with European and French law and institutional ethical guidelines. (17)…”

The exogenous delivery of microRNA-449b-5p using spermidine-PLGA nanoparticles efficiently decreases hepatic injury

“…17,18 Similarly, miR-449b-5p has been reported to be under-expressed in liver cancer and inhibits cell proliferation and cell migration. 19 The 3 0 -UTR of HMGB1 contains the site for miR-449b-5p binding, and therefore, miR-449b-5p has been predicted to be involved in the hepatic I/R injury by controlling HMGB1 and can be a potential target in the effective treatment of liver diseases. 20 However, unmodied miRNA is highly unstable in the systemic circulation due to its enzymatic degradation, resulting in its poor therapeutic efficacy.…”

Serum exosomal microRNA let‐7i‐3p as candidate diagnostic biomarker for Kawasaki disease patients with coronary artery aneurysm

“…RAF1 reduction mediated by let‐7i‐3p plays a role in melatonin inhibition of hepatocellular carcinoma . Indersie et al reported that let‐71‐3p, miR‐449b‐3p, and miR‐885‐5p were decreased in tumors compared to normal livers, and that these miRNAs inhibited HBL cell grow and Wnt signaling activity in vitro, partly through beta‐catenin downregulation . Some studies predicted the potential target genes of let‐7i‐3p and its involvement in various cellular pathways .…”