Targeting microRNA-145-mediated progressive phenotypes of early bladder cancer in a molecularly defined in vivo model

Kazuki Heishima; Nobuhiko Sugito; Chikara Abe; Akihiro Hirata; Hiroki Sakai; Yukihiro Akao

doi:10.1016/j.omtn.2023.06.009

Targeting microRNA-145-mediated progressive phenotypes of early bladder cancer in a molecularly defined in vivo model

Mol Ther Nucleic Acids. 2023 Jul 3:33:960-982. doi: 10.1016/j.omtn.2023.06.009. eCollection 2023 Sep 12.

Authors

Kazuki Heishima^{1

2

3}, Nobuhiko Sugito¹, Chikara Abe⁴, Akihiro Hirata^{3

5}, Hiroki Sakai^{3

5}, Yukihiro Akao¹

Affiliations

¹ The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Gifu, Japan.
² Institute for Advanced Study (GUiAS), Gifu University, Gifu, Gifu, Japan.
³ Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Gifu, Japan.
⁴ Department of Physiology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
⁵ Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.

Abstract

A progressive subclass of early-stage non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progress into invasive carcinoma, thus decreasing the overall survival rate of NMIBC. However, therapeutic development for progressive NMIBC has been challenging due to the lack of molecularly validated in vivo models and agents targeting its genetic vulnerability. We herein molecularly characterized an interventional model of progressive NMIBC and revealed the principal functions and therapeutic potential of microRNA-145 (miR-145) in early bladder tumorigenesis. N-butyl-N-(4-hydroxybutyl)nitrosamine-induced premalignant lesions (BiPLs) in rats exhibited downregulated expression of miR-145 as well as highly similar mutation/expression profiles to those of the human progressive NMIBC subclass with the worst prognosis. The expression patterns of miR-145 inversely correlated with those of BC-related oncogenes in BiPLs. We also demonstrated that miR-145 dominantly regulated interferon pathways and c-Myc expression, which play a crucial role in the pathogenesis of progressive NMIBC. Furthermore, we demonstrated that miR-145 replacement with a novel miR-145-based intravesical agent (miR-145S1) significantly inhibited the progression of BiPLs in vivo. These results provide insights into the essential role of miR-145 as the earliest-acting oncogenic driver of bladder tumorigenesis as well as a validated interventional model and novel miR-145-based nucleic acid therapeutic agent for progressive NMIBC.

Keywords: MT: Non-coding RNAs; NMIBC; early bladder cancer; early bladder cancer rat model; intravesical therapy; microRNA; microRNA-145; non-muscle-invasive bladder cancer.