Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

作者：A‐Bin You, Manqing Cao, Zhigui Guo, Bingfeng Zuo, Junrong Gao, Hongyuan Zhou, Huikai Li, Yunlong Cui, Fang Fěng, Wei Zhang, Tianqiang Song, Qiang Li, Xiaolin Zhu, HaiFang Yin, Hui‐Chuan Sun, Ti Zhang · 发表于：Journal of Hematology & Oncology · 年份：2016 · DOI：10.1186/s13045-016-0253-6 · 被引用次数：79 · 研究领域：Metabolism, Diabetes, and Cancer、Cancer, Hypoxia, and Metabolism、Mechanisms of cancer metastasis

BACKGROUND: Sorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy. METHODS: The protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2α and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry. RESULTS: Our study demonstrated that metformin synergized with sorafenib reduced HIF-2α expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated...