A tumor endothelial cell-specific microRNA replacement therapy for hepatocellular carcinoma

Hideki Iwamoto; Hiroyuki Suzuki; Atsutaka Masuda; Takahiko Sakaue; Toru Nakamura; Toshimitsu Tanaka; Miwa Sakai; Yasuko Imamura; Hirohisa Yano; Takuji Torimura; Hironori Koga; Kaori Yasuda; Masakatsu Tsurusaki; Takahiro Seki; Takumi Kawaguchi

doi:10.1016/j.isci.2024.108797

A tumor endothelial cell-specific microRNA replacement therapy for hepatocellular carcinoma

iScience. 2024 Jan 4;27(2):108797. doi: 10.1016/j.isci.2024.108797. eCollection 2024 Feb 16.

Authors

Hideki Iwamoto^{1

2

3}, Hiroyuki Suzuki^{1

2}, Atsutaka Masuda^{1

2}, Takahiko Sakaue^{1

2}, Toru Nakamura^{1

2}, Toshimitsu Tanaka^{1

2}, Miwa Sakai¹, Yasuko Imamura^{1

2}, Hirohisa Yano⁴, Takuji Torimura^{1

2}, Hironori Koga^{1

2}, Kaori Yasuda⁵, Masakatsu Tsurusaki⁶, Takahiro Seki⁷, Takumi Kawaguchi^{1

2}

Affiliations

¹ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 831 0011, Japan.
² Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 831 0011, Japan.
³ Department of Medicine, Iwamoto Internal Medicine Clinic, Kitakyushu 802 0832, Japan.
⁴ Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan.
⁵ Cell Innovator, Inc., Venture Business Laboratory of Kyushu University, Fukuoka 812-8582, Japan.
⁶ Department of Radiology, Kindai University Faculty of Medicine, Osaka-Sayama 589 8511, Japan.
⁷ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Solna, Sweden.

Abstract

Current approved anti-angiogenic drugs (AAD) for hepatocellular carcinoma (HCC) inhibit tumor angiogenesis, but affect the hepatic vasculature resulting in adverse effects. Tumor endothelial cells (TECs) differ from normal endothelial cells. In this study, we aimed to detect TEC-specific miRNAs and develop an anti-angiogenic treatment specific for TECs. We established HCC orthotopic mouse models. TEC-specific miRNAs were detected using a microRNA array. Finally, we evaluated the therapeutic effects of the TEC-specific miRNA agonist cocktail. In total, 260 TEC-specific genes were detected. Among the top ten downregulated TEC-specific miRNAs, miR-139-3p and 214-3p were important for the TEC phenotype. The TEC-specific microRNA agonist cocktail showed significant anti-tumor effects by inhibiting tumor angiogenesis without affecting hepatic vasculatures in HCC orthotopic mouse models. Moreover, it significantly downregulated tip-cell sprouting-related genes. We identified two downregulated TEC-specific miRNAs; microRNA replacement therapy, which targets the downregulated TEC-specific miRNAs, is an effective and promising treatment for HCC.

Keywords: Cancer; Molecular biology.