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

Autor: A-Bin You, Hongyuan Zhou, Xiaolin Zhu, Wei Zhang, Tianqiang Song, Ti Zhang, Huikai Li, Bingfeng Zuo, Qiang Li, Yunlong Cui, Hui-Chuan Sun, Junrong Gao, Zhigui Guo, Man-Qing Cao, Haifang Yin, Feng Fang
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Oncology
Male
Cancer Research
Hepatocellular carcinoma
Apoptosis
Metastasis
0302 clinical medicine
Hypoxia-inducible factors
Antineoplastic Combined Chemotherapy Protocols
Basic Helix-Loop-Helix Transcription Factors
Neoplasm Metastasis
Mice
Inbred BALB C
Liver Neoplasms
Drug Synergism
lcsh:Diseases of the blood and blood-forming organs
Hematology
Sorafenib
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Metformin
Cell Hypoxia
Blot
030220 oncology & carcinogenesis
medicine.drug
Niacinamide
medicine.medical_specialty
Carcinoma
Hepatocellular
Epithelial-Mesenchymal Transition
Cell Survival
Blotting
Western
Mice
Nude
Antineoplastic Agents
lcsh:RC254-282
03 medical and health sciences
Acetyltransferases
Internal medicine
Cell Line
Tumor
medicine
Animals
Humans
Hypoglycemic Agents
Viability assay
Molecular Biology
neoplasms
TIP30
Cell Proliferation
lcsh:RC633-647.5
Cell growth
business.industry
Research
Phenylurea Compounds
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
030104 developmental biology
Cancer research
Neoplasm Recurrence
Local
business
Transcription Factors
Zdroj: Journal of Hematology & Oncology
Journal of Hematology & Oncology, Vol 9, Iss 1, Pp 1-9 (2016)
ISSN: 1756-8722
Popis: 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 after knocking-down of HIF-2α and chromatin immunoprecipitation assay revealed that HIF-2α could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression. Conclusions Metformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0253-6) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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