Loss of 11βHSD1 enhances glycolysis, facilitates intrahepatic metastasis, and indicates poor prognosis in hepatocellular carcinoma
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Xu Liu1,2, Xiao-long Tan1, Meng Xia1, Chao Wu1, Jia Song1, Jing-jing Wu1, Arian Laurence3, Qing-guo Xie4, Ming-zhi Zhang5, Hui-fang Liang1,*, Bi-xiang Zhang1,* and Xiao-ping Chen1,*
1 Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
2 Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
3 The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
4 Department of Biomedical Engineering, and Wuhan National Laboratory for Optoelectronics (WNLO), Huazhong University of Science and Technology, Wuhan, Hubei, China
5 Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
* These authors have contributed equally to this work
Hui-fang Liang, email:
Bi-xiang Zhang, email:
Xiao-ping Chen, email:
Keywords: 11beta-hydroxysteroid dehydrogenase type 1, aerobic glycolysis, hepatocellular carcinoma, intrahepatic metastasis, prognostic biomarker
Received: June 24, 2015 Accepted: November 21, 2015 Published: December 18, 2015
11Beta-hydroxysteroid dehydrogenase type 1 (11βHSD1), converting glucocorticoids from hormonally inactive cortisone to active cortisol, plays an essential role in glucose homeostasis. Accumulating evidence suggests that enhanced glycolytic activity is closely associated with postoperative recurrence and prognosis of hepatocellular carcinoma (HCC). Whether 11βHSD1 contributes to HCC metastasis and recurrence remains unclear. Here we found that expression of 11βHSD1 in human HCC (310 pairs) was frequently decreased compared to the adjacent non-neoplastic liver tissues (ANT), which correlated well with the intrahepatic-metastatic index, serum glycemia, and other malignant clinicopathological characteristics of HCC and predicted poor prognosis. Knockdown of 11βHSD1 in BEL-7402 cells drastically reduced the pH of culture medium and induced cell death. Meanwhile, overexpression of 11βHSD1 in SMMC-7721 HCC cells resulted in repression of cell migration, invasion, angiogenesis, and proliferation in vitro. When transferred into BALB/c nude mice, 11βHSD1 overexpression resulted in decreased intrahepatic metastasis, angiogenesis, and tumor size. F-18-2-fluoro-2-deoxyglucose accumulation assay measured by positron emission tomography elucidated that 11βHSD1 reduced glucose uptake and glycolysis in SMMC-7721 cells in vitro, and intrahepatic metastasis foci and subcutaneous tumor growth in vivo. We showed that 11βHSD1 repressed cell metastasis, angiogenesis and proliferation of HCC by causing disruption of glycolysis via the HIF-1α and c-MYC pathways. In conclusion, 11βHSD1 inhibits the intrahepatic metastasis of HCC via restriction of tumor glycolysis activity and may serve as a prognostic biomarker for patients.
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