MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway

Taisuke Obata; Koichiro Tsutsumi; Eijiro Ueta; Takashi Oda; Tatsuya Kikuchi; Soichiro Ako; Yuki Fujii; Tatsuhiro Yamazaki; Daisuke Uchida; Kazuyuki Matsumoto; Shigeru Horiguchi; Hironari Kato; Hiroyuki Okada; Motoyuki Otsuka

doi:10.1016/j.omtn.2023.102054

MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway

Mol Ther Nucleic Acids. 2023 Oct 28:34:102054. doi: 10.1016/j.omtn.2023.102054. eCollection 2023 Dec 12.

Authors

Affiliations

¹ Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama 700-8558, Japan.
² Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama 700-8558, Japan.

Abstract

Gemcitabine is an effective chemotherapeutic agent for biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA). However, few other effective agents are currently available, particularly for GEM-refractory BTCs. We previously identified microRNA-451a (miR-451a) as a potential therapeutic target in GBC. To elucidate the antineoplastic effects of miR-451a and its underlying mechanisms, we transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cell lines. Furthermore, mimicking in vivo conditions, tumorigenic GBC organoids and three-dimensional (3D) cell culture systems were employed to investigate the anti-proliferative effects of miR-451a on BTCs, and its effect on stem cell properties. We found that miR-451a significantly inhibited cell proliferation, induced apoptosis, and reduced chemoresistant phenotypes, such as epithelial-mesenchymal transition, in both GBC and GR-GBC. The principal mechanism is probably the negative regulation of the phosphatidylinositol 3-kinase/AKT pathway, partially accomplished by directly downregulating macrophage migration inhibitory factor. The Gene Expression Omnibus database revealed that miR-451a was the most significantly downregulated microRNA in CCA tissues. The introduction of miR-451a resulted in similar antineoplastic effects in GR-CCA. Furthermore, miR-451a reduced cell viability in 3D spheroid models and tumorigenic GBC organoids. These findings suggest that the supplementation of miR-451a is a potential treatment strategy for GEM-refractory BTCs.

Keywords: MT: Oligonucleotides: Therapies and Applications; biliary tract cancer; cholangiocarcinoma; gallbladder cancer; gemcitabine; nucleic acid-based therapy.