Research Papers:

Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine

Takahiro Kishikawa _, Motoyuki Otsuka, Tan Poh Seng, Motoko Ohno, Xiaochen Sun, Takeshi Yoshikawa, Chikako Shibata, Akemi Takata, Kentaro Kojima, Kenji Takehana, Maki Ohishi, Sana Ota, Tomoyuki Noyama, Yuji Kondo, Masaya Sato, Tomoyoshi Soga, Yujin Hoshida and Kazuhiko Koike

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Oncotarget. 2015; 6:8339-8352. https://doi.org/10.18632/oncotarget.3234

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Takahiro Kishikawa1, Motoyuki Otsuka1,2, Poh Seng Tan3,4, Motoko Ohno1, Xiaochen Sun3, Takeshi Yoshikawa1, Chikako Shibata1, Akemi Takata1, Kentaro Kojima1, Kenji Takehana5, Maki Ohishi6, Sana Ota6, Tomoyuki Noyama1, Yuji Kondo1, Masaya Sato1, Tomoyoshi Soga5, Yujin Hoshida3, Kazuhiko Koike1

1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113–8655, Japan

2Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama 332–0012, Japan

3Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA

4Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, 119228, Singapore

5Pharmacology Research Laboratory, Research Institute, Ajinomoto Pharmaceutical Co., Ltd., Kawasaki, Kanagawa 210–8681, Japan

6Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997–0052, Japan

Correspondence to:

Motoyuki Otsuka, e-mail: [email protected]

Keywords: HCC, miR122, SLC7A1, nitric oxide, arginine

Received: January 26, 2015     Accepted: January 28, 2015     Published: March 21, 2015


Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122-silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

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