Antitumor effects of chemically modified miR-143 lipoplexes in a mouse model of pelvic colorectal cancer via myristoylated alanine-rich C kinase substrate downregulation

Jun Arima; Kohei Taniguchi; Nobuhiko Sugito; Kazuki Heishima; Yoshihisa Tokumaru; Yosuke Inomata; Kazumasa Komura; Tomohito Tanaka; Masa-Aki Shibata; Sang-Woong Lee; Yukihiro Akao

doi:10.1016/j.omtn.2023.102079

Antitumor effects of chemically modified miR-143 lipoplexes in a mouse model of pelvic colorectal cancer via myristoylated alanine-rich C kinase substrate downregulation

Mol Ther Nucleic Acids. 2023 Nov 15:34:102079. doi: 10.1016/j.omtn.2023.102079. eCollection 2023 Dec 12.

Authors

Affiliations

¹ Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
² Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
³ United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁴ Institute for Advanced Study, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁵ Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁶ Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.

Abstract

Replenishing tumor-suppressor miRNAs (TS-miRNAs) is a potential next-generation nucleic acid-based therapeutic approach. Establishing an effective miRNA delivery system is essential to successful TS-miRNA therapy. To overcome vulnerability to RNA nucleases, we previously developed a chemically modified miRNA143-3p (CM-miR-143). In clinical practice, colorectal cancer (CRC) pelvic recurrence is an occasional challenge following curative resection, requiring a novel therapy because reoperative surgery poses a significant burden to the patient. Hence, we considered the use of CM-miR-143 as an alternative treatment. In this study, we used a mouse model bearing pelvic CRC adjacent to the rectum and investigated the anticancer effects of CM-miR-143 lipoplexes formulated from miRNA and a cationic liposome. Compared with commercial synthetic miR-143, CM-miR-143 lipoplexes accumulated heavily in regions of the pelvic CRC tumor where the blood flow was high. As a result, systemic administration of CM-miR-143 lipoplexes improved animal survival by significantly suppressing pelvic CRC tumors and relieving a lethal bowel obstruction caused by rectal compression. Detailed protein analysis revealed that the myristoylated alanine-rich C kinase is a novel target for CM-miR-143 lipoplexes. Our results suggest that CM-miR-143 is a potential next-generation drug candidate in the treatment of CRC pelvic recurrence.

Keywords: CRC; MARCKS; MT: noncoding RNAs; colorectal cancer; lipoplexes; miR-143; miRNA-143; pelvic recurrence.