Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo

Miyoshi,Hisaaki; Kato,Kiyohito; Iwama,Hisakazu; Maeda,Emiko; Sakamoto,Teppei; Fujita,Koji; Toyota,Yuka; Tani,Joji; Nomura,Takako; Mimura,Shima; Kobayashi,Mitsuyoshi; Morishita,Asahiro; Kobara,Hideki; Mori,Hirohito; Yoneyama,Hirohito; Deguchi,Akihiro; Himoto,Takashi; Kurokohchi,Kazutaka; Okano,Keiichi; Suzuki,Yasuyuki; Murao,Koji; Masaki,Tsutomu

doi:10.3892/ijo.2014.2419

Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo

Authors:
- Hisaaki Miyoshi
- Kiyohito Kato
- Hisakazu Iwama
- Emiko Maeda
- Teppei Sakamoto
- Koji Fujita
- Yuka Toyota
- Joji Tani
- Takako Nomura
- Shima Mimura
- Mitsuyoshi Kobayashi
- Asahiro Morishita
- Hideki Kobara
- Hirohito Mori
- Hirohito Yoneyama
- Akihiro Deguchi
- Takashi Himoto
- Kazutaka Kurokohchi
- Keiichi Okano
- Yasuyuki Suzuki
- Koji Murao
- Tsutomu Masaki
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Affiliations: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan, Life Science Research Center, Faculty of Medicine, Kagawa University, Kagawa, Japan, Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan, Department of Laboratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
Published online on: May 6, 2014 https://doi.org/10.3892/ijo.2014.2419
Pages: 322-332

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Abstract

Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle‑related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.

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