Oncotarget

Research Papers:

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice

Koki Obara, Yohei Shirakami _, Akinori Maruta, Takayasu Ideta, Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Takuji Tanaka, Mitsuru Seishima and Masahito Shimizu

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Oncotarget. 2017; 8:58353-58363. https://doi.org/10.18632/oncotarget.16874

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Abstract

Koki Obara1, Yohei Shirakami1,2, Akinori Maruta1, Takayasu Ideta1, Tsuneyuki Miyazaki1, Takahiro Kochi1, Hiroyasu Sakai1, Takuji Tanaka3, Mitsuru Seishima2 and Masahito Shimizu1

1Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan

2Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan

3Department of Pathological Diagnosis, Gifu Municipal Hospital, Gifu, Japan

Correspondence to:

Yohei Shirakami, email: ys2443@gifu-u.ac.jp

Keywords: sodium glucose cotransporter 2 (SGLT2), hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), obesity, diabetes mellitus

Received: November 01, 2016     Accepted: March 11, 2017     Published: April 06, 2017

ABSTRACT

Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.


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