ArticleJournal of hematology & oncology2016
Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models.
Article in Journal of hematology & oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 77 citations in OpenAlex.
- Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.Nature communications · 2026Article
- Metabolic burden-based clinical-radiological model for predicting postoperative recurrence of hepatitis B-related hepatocellular carcinoma.Insights into imaging · 2026Article
- Research Progress on the Molecular Mechanism of Metformin Regulating AMPK Signaling Pathway in Inhibiting Liver Cancer.OncoTargets and therapy · 2026Review
- Review
- Neoadjuvant immunotherapy for resectable primary liver cancer (Review).Oncology letters · 2025Review
- Mechanisms of drug resistance in hepatocellular carcinoma.Biological procedures online · 2025Review
- Advances in the Use of Metformin for Liver Disease.Current medicinal chemistry · 2025Review
- Ferroptosis-inducing nanomedicine and targeted short peptide for synergistic treatment of hepatocellular carcinoma.Journal of nanobiotechnology · 2024Article
- Enhanced anti-tumor therapy for hepatocellular carcinoma via sorafenib and KIAA1199-siRNA co-delivery liposomes.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2024Article
- Phosphorylated FOXQ1, a novel substrate of JNK1, inhibits sorafenib-induced ferroptosis by activating ETHE1 in hepatocellular carcinoma.Cell death & disease · 2024Article
- Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review).American journal of cancer research · 2024Review
- Metformin promotes ferroptosis and sensitivity to sorafenib in hepatocellular carcinoma cells via ATF4/STAT3.Molecular biology reports · 2023Article
- CMTR1 promotes colorectal cancer cell growth and immune evasion by transcriptionally regulating STAT3.Cell death & disease · 2023Article
- Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy.Cellular & molecular immunology · 2023Review
- Article
- Potential Treatment Strategies for Hepatocellular Carcinoma Cell Sensitization to Sorafenib.Journal of hepatocellular carcinoma · 2023Review
- [Sorafenib regulates vascular endothelial growth factor by runt-related transcription factor-3 to inhibit angiogenesis in hepatocellular carcinoma].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2022Article
- Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism.International journal of molecular sciences · 2022Article
- Role of metformin in the diagnosis, prevention, and treatment of hepatocellular carcinoma.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2022Article
- Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).The oncologist · 2022Article
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSorafenib 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.
methodsThe 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.
resultsOur 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.
conclusionsMetformin 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.
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