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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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Perazza F, Leoni L, Colosimo S, Musio A, Bocedi G, D’Avino M, Agnelli G, Nicastri A, Rossetti C, Sacilotto F, Marchesini G, Petroni ML, Ravaioli F. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites 2024; 14:186. [PMID: 38668314 PMCID: PMC11052067 DOI: 10.3390/metabo14040186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.
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Affiliation(s)
- Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Laura Leoni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Santo Colosimo
- Doctorate School of Nutrition Science, University of Milan, 20122 Milan, Italy;
| | | | - Giulia Bocedi
- U.O. Diabetologia, Ospedale C. Magati, Scandiano, 42019 Reggio Emilia, Italy;
| | - Michela D’Avino
- S.C. Endocrinologia Arcispedale Santa Maria Nuova, 42123 Reggio Emilia, Italy;
| | - Giulio Agnelli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Alba Nicastri
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Chiara Rossetti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federica Sacilotto
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Giulio Marchesini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
- Division of Hepatobiliary and Immunoallergic Diseases, Department of Internal Medicine, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
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Franco-Juárez EX, González-Villasana V, Camacho-Moll ME, Rendón-Garlant L, Ramírez-Flores PN, Silva-Ramírez B, Peñuelas-Urquides K, Cabello-Ruiz ED, Castorena-Torres F, Bermúdez de León M. Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:1760. [PMID: 38339037 PMCID: PMC10855535 DOI: 10.3390/ijms25031760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.
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Affiliation(s)
- Edgar Xchel Franco-Juárez
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Vianey González-Villasana
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - María Elena Camacho-Moll
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
| | - Luisa Rendón-Garlant
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Patricia Nefertari Ramírez-Flores
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico;
| | - Beatriz Silva-Ramírez
- Departamento de Inmunogenética, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico;
| | - Katia Peñuelas-Urquides
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
| | - Ethel Daniela Cabello-Ruiz
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Fabiola Castorena-Torres
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico;
| | - Mario Bermúdez de León
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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Ruan G, Wu F, Shi D, Sun H, Wang F, Xu C. Metformin: update on mechanisms of action on liver diseases. Front Nutr 2023; 10:1327814. [PMID: 38192642 PMCID: PMC10773879 DOI: 10.3389/fnut.2023.1327814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024] Open
Abstract
Substantial attention has been paid to the various effects of metformin on liver diseases; the liver is the targeted organ where metformin exerts its antihyperglycemic properties. In non-alcoholic fatty liver disease (NAFLD), studies have shown that metformin affects the ATP/AMP ratio to activate AMPK, subsequently governing lipid metabolism. The latest research showed that low-dose metformin targets the lysosomal AMPK pathway to decrease hepatic triglyceride levels through the PEN2-ATP6AP1 axis in an AMP-independent manner. Metformin regulates caspase-3, eukaryotic initiation factor-2a (eIF2a), and insulin receptor substrate-1 (IRS-1) in palmitate-exposed HepG2 cells, alleviating endoplasmic reticulum (ER) stress. Recent observations highlighted the critical association with intestinal flora, as confirmed by the finding that metformin decreased the relative abundance of Bacteroides fragilis while increasing Akkermansia muciniphila and Bifidobacterium bifidum. The suppression of intestinal farnesoid X receptor (FXR) and the elevation of short-chain fatty acids resulted in the upregulation of tight junction protein and the alleviation of hepatic inflammation induced by lipopolysaccharide (LPS). Additionally, metformin delayed the progression of cirrhosis by regulating the activation and proliferation of hepatic stellate cells (HSCs) via the TGF-β1/Smad3 and succinate-GPR91 pathways. In hepatocellular carcinoma (HCC), metformin impeded the cell cycle and enhanced the curative effect of antitumor medications. Moreover, metformin protects against chemical-induced and drug-induced liver injury (DILI) against hepatotoxic drugs. These findings suggest that metformin may have pharmacological efficacy against liver diseases.
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Affiliation(s)
- Gaoyi Ruan
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangquan Wu
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Dibang Shi
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongxia Sun
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Fangyan Wang
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Changlong Xu
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med 2023; 21:403. [PMID: 37344841 DOI: 10.1186/s12967-023-04263-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023] Open
Abstract
Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.
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Affiliation(s)
- Yu Hua
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yue Zheng
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
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Papadakos SP, Ferraro D, Carbone G, Frampton AE, Vennarecci G, Kykalos S, Schizas D, Theocharis S, Machairas N. The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy? Cancers (Basel) 2023; 15:3161. [PMID: 37370771 PMCID: PMC10295995 DOI: 10.3390/cancers15123161] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Daniele Ferraro
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Gabriele Carbone
- Department of General Surgery and Organ Transplantation, University of Rome “Sapienza”, 00161 Rome, Italy;
| | - Adam Enver Frampton
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK;
- Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, UK
- HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford GU2 7XX, UK
| | - Giovanni Vennarecci
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Stylianos Kykalos
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
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Rosidi B, Priyatno D, Putra TP, Yusuf I. Metformin Induces a Caspase 3-Unrelated Apoptosis in Human Colorectal Cancer Cell Lines HCT116 and SW620. Cancer Manag Res 2023; 15:475-485. [PMID: 37312884 PMCID: PMC10259592 DOI: 10.2147/cmar.s385278] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 03/16/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose To study the effects of metformin on the proliferation and growth of human colorectal cancer cell lines HCT116 and SW620. Materials and Methods The antiproliferative effect of metformin was assayed using an MTS reagent and its ability to inhibit colony formation was demonstrated using a clonogenic assay. Flow cytometry using YO-PRO-1/PI was performed to examine the effects of metformin on apoptosis and cell death of HCT116 and SW620. Caspase 3 activities were measured in caspase-3 activity tests using a caspase-3 activity kit. Furthermore, Western blots were performed with anti-PARP1, anti-caspase 3, and anti-cleaved caspase 3 to confirm whether caspase activation was present or not. Results Both MTS proliferation assays and clonogenic assays showed that metformin inhibited the proliferation and growth of HCT116 and SW620 cells in a concentration-dependent manner. Flow cytometric analysis identified early apoptosis and metformin-induced cell death in both cell lines. However, caspase 3 activity could not be detected. Cleavage of both PARP1 and pro-caspase 3 was not observed in the Western blot, confirming the absence of caspase 3 activations. Conclusion This present study suggests a caspase 3-unrelated apoptosis mechanism of metformin-induced cell death in human colorectal cancer cell lines HCT116 and SW620.
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Affiliation(s)
- Bustanur Rosidi
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Diana Priyatno
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Teguh Pribadi Putra
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Irawan Yusuf
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
- Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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10
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Fornari F, Giovannini C, Piscaglia F, Gramantieri L. Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research. J Hepatocell Carcinoma 2022; 9:1263-1278. [PMID: 36523954 PMCID: PMC9744868 DOI: 10.2147/jhc.s347946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 11/23/2022] [Indexed: 01/11/2025] Open
Abstract
In the last decade, relevant advances have occurred in the treatment of hepatocellular carcinoma (HCC), with novel drugs entering the clinical practice, among which tyrosine kinase inhibitors (TKIs) such as lenvatinib, cabozantinib and regorafenib, and immune checkpoint inhibitors (ICPIs) either alone or in combination with VEGF inhibitors. Clinical trials have driven the introduction of such novel molecules into the clinics but, at present, no biomarker drives the choice of first-line options, which relies only upon clinical and imaging assessment. Remarkably, clinical and imaging-based evaluations do not consider the huge heterogeneity of HCC and do not allow to realize the potential of personalized treatments. Preclinical research still does not inform the design of clinical trials, even though many animal models mimicking specific subgroups of HCC are available and might provide relevant information. Although animal models directly informing the clinical practice, such as patients-derived xenografts, are not used to help the choice of treatment in advanced HCC, however, the preclinical research can count on a wide range of valuable models. Here we will review some HCC models which might turn informative for specific questions in defined patient subgroups, and we will describe recent preclinical studies for the mechanistic evaluation of immunotherapy-based treatment approaches. To this aim, we will mainly focus on two issues: (i) HCC models informative on NAFLD-NASH HCC and (ii) HCC models helping to elucidate mechanisms underneath immunotherapy. We have chosen these two settings since they represent, respectively, the most rapidly arising cause of chronic liver disease (CLD) and HCC in western countries and the most promising therapeutic option for advanced HCC.
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Affiliation(s)
- Francesca Fornari
- Centre for Applied Biomedical Research - CRBA, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department for Life Quality Studies, University of Bologna, Rimini, Italy
| | - Catia Giovannini
- Centre for Applied Biomedical Research - CRBA, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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11
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Cruciani S, Garroni G, Pala R, Coradduzza D, Cossu ML, Ginesu GC, Capobianco G, Dessole S, Ventura C, Maioli M. Metformin and vitamin D modulate adipose-derived stem cell differentiation towards the beige phenotype. Adipocyte 2022; 11:356-365. [PMID: 35734882 PMCID: PMC9235891 DOI: 10.1080/21623945.2022.2085417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022] Open
Abstract
Adipose-derived stem cells (ADSCs) represent an ideal stem cell population for regenerative medicine. ADSC adipogenic differentiation is controlled by the activation of a specific transcriptional program, including epigenetic factors and key adipogenic genes. Under certain conditioned media, ADSCs can differentiate into several phenotypes. We previously demonstrated that bioactive molecules could counteract lipid accumulation and regulate adipogenesis, acting on inflammation and vitamin D metabolism. In the present paper, we aimed at evaluating the effect of metformin and vitamin D in targeting ADSC differentiation towards an intermediate phenotype, as beige adipocytes. We exposed ADSCs to different conditioned media and then we evaluated the levels of expression of main markers of adipogenesis, aP2, LPL and ACOT2. We also analysed the gene and protein expression of thermogenic UCP1 protein, and the expression of PARP1 and the beige specific marker TMEM26. Our results showed a novel effect of metformin and vitamin D not only in inhibiting adipogenesis, but also in inducing a specific 'brown-like' phenotype. These findings pave the way for their possible application in the control of de novo lipogenesis useful for the prevention of obesity and its related metabolic disorders.
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Affiliation(s)
- Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Giuseppe Garroni
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Renzo Pala
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | | | - Maria Laura Cossu
- General Surgery Unit 2 “Clinica Chirurgica” Medical, Surgical and Experimental Sciences Department, University of Sassari, Sassari, Italy
| | - Giorgio Carlo Ginesu
- General Surgery Unit 2 “Clinica Chirurgica” Medical, Surgical and Experimental Sciences Department, University of Sassari, Sassari, Italy
| | - Giampiero Capobianco
- Department of Medical, Surgical and Experimental Sciences, Gynecologic and Obstetric Clinic, University of Sassari, Sassari, Italy
| | - Salvatore Dessole
- Department of Medical, Surgical and Experimental Sciences, Gynecologic and Obstetric Clinic, University of Sassari, Sassari, Italy
| | - Carlo Ventura
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems - Eldor Lab, Innovation Accelerator, Consiglio Nazionale delle Ricerche, Bologna, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Sassari, Italy
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12
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Ramadan A, Abdelaziz AO, Sabry D, Fathi SAET, Nabeel MM, Shousha HI, Elbaz TM, Lithy RM, Ryed HR. Study on molecular expression of long non-coding RNA Glypican3 in hepatocellular cancer patients. EGYPTIAN LIVER JOURNAL 2022; 12:58. [DOI: 10.1186/s43066-022-00221-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 09/29/2022] [Indexed: 04/19/2025] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is one of the main cancers in the world with a high mortality rate. The molecular mechanisms of HCC are poorly understood. Long non-coding RNAs (lncRNAs) have a role in HCC pathogenesis. Glypican3 (GPC3) is a cell surface oncofetal proteoglycan that is expressed in HCC, and its overexpression predicts a poorer prognosis. We aimed to assess the levels of alfa fetoprotein (AFP), lncRNA AF085935 gene expression, and GPC3 protein in HCC patients.
Patients and methods
The patients were classified into three groups: HCC group, cirrhotic group, and healthy control group. For all groups, we performed clinical examinations, laboratory investigations, and imaging. The levels of AFP, GPC3 protein, and LncRNA gene expression were estimated. A statistical analysis was done.
Results
Levels of GPC3 and LncRNA gene expression were significantly higher in the HCC group versus other groups. LncRNA gene and GPC3 levels are excellent for the detection of HCC with a sensitivity of 96% and 87%, respectively. Specificity was 81% and 64%, respectively. Linear regression analysis showed that LncRNA gene expression and GPC3 protein are significant predictors for HCC (p = 0 and p = 0.001, respectively). Log rank analysis based on GPC3 and LncRNA gene expression levels in HCC patients showed that high expression of GPC3 and LncRNA is associated with shorter overall survival than those with low expressions (p value < 0.001).
Conclusion
In our study, LncRNA gene expression and GPC3 levels are good diagnostic and prognostic biomarkers for HCC patients.
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13
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Suter P, Dazert E, Kuipers J, Ng CKY, Boldanova T, Hall MN, Heim MH, Beerenwinkel N. Multi-omics subtyping of hepatocellular carcinoma patients using a Bayesian network mixture model. PLoS Comput Biol 2022; 18:e1009767. [PMID: 36067230 PMCID: PMC9481159 DOI: 10.1371/journal.pcbi.1009767] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 09/16/2022] [Accepted: 07/18/2022] [Indexed: 11/18/2022] Open
Abstract
Comprehensive molecular characterization of cancer subtypes is essential for predicting clinical outcomes and searching for personalized treatments. We present bnClustOmics, a statistical model and computational tool for multi-omics unsupervised clustering, which serves a dual purpose: Clustering patient samples based on a Bayesian network mixture model and learning the networks of omics variables representing these clusters. The discovered networks encode interactions among all omics variables and provide a molecular characterization of each patient subgroup. We conducted simulation studies that demonstrated the advantages of our approach compared to other clustering methods in the case where the generative model is a mixture of Bayesian networks. We applied bnClustOmics to a hepatocellular carcinoma (HCC) dataset comprising genome (mutation and copy number), transcriptome, proteome, and phosphoproteome data. We identified three main HCC subtypes together with molecular characteristics, some of which are associated with survival even when adjusting for the clinical stage. Cluster-specific networks shed light on the links between genotypes and molecular phenotypes of samples within their respective clusters and suggest targets for personalized treatments.
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Affiliation(s)
- Polina Suter
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Eva Dazert
- Biozentrum, University of Basel, Basel, Switzerland
| | - Jack Kuipers
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Charlotte K. Y. Ng
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Tuyana Boldanova
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | | | - Markus H. Heim
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- * E-mail:
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Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23158083. [PMID: 35897659 PMCID: PMC9329836 DOI: 10.3390/ijms23158083] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
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15
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Cozma GV, Apostu A, Macasoi I, Dehelean CA, Cretu OM, Dinu S, Gaiță D, Manea A. In Vitro and In Ovo Evaluation of the Potential Hepatoprotective Effect of Metformin. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:705. [PMID: 35743967 PMCID: PMC9228172 DOI: 10.3390/medicina58060705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 11/16/2022]
Abstract
Background and Objectives: Metformin is currently the leading drug of choice for treating type 2 diabetes mellitus, being one of the most widely used drugs worldwide. The beneficial effects of Metformin, however, extend far beyond the reduction of blood glucose. Therefore, this study aimed to evaluate Metformin's effects both in vitro and in ovo. Materials and Methods: Metformin has been tested in five different concentrations in human hepatocytes -HepaRG, in terms of cell viability, morphology, structure and number of nuclei and mitochondria, as well as the effect on cell migration. Through the application of HET-CAM, the biocompatibility and potential anti-irritant, as well as protective effects on the vascular plexus were also assessed. Results: According to the results obtained, Metformin increases cell viability without causing morphological changes to cells, mitochondria, or nuclei. Metformin displayed an anti-irritant activity rather than causing irritation at the level of the vascular plexus. Conclusions: In conclusion, Metformin enhances cell viability and proliferation and, has a protective effect on the vascular plexus. Nonetheless, more studies are required to clarify the mechanism of hepatoprotective effect of metformin.
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Affiliation(s)
- Gabriel Veniamin Cozma
- Department of Surgical Semiology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania;
| | - Alexandru Apostu
- Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 49 No., C. D. Loga Bv., 300041 Timişoara, Romania; (A.A.); (D.G.)
- Advanced Research Center of the Institute for Cardiovascular Diseases, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Ioana Macasoi
- Departament of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Cristina Adriana Dehelean
- Departament of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Octavian Marius Cretu
- Department of Surgery, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania;
| | - Stefania Dinu
- Department of Pedodontics, Faculty of Dental Medicine, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 9 No., Revolutiei Bv., 300041 Timişoara, Romania;
- Pediatric Dentistry Research Center, Faculty of Dental Medicine, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 9 No., Revolutiei Bv., 300041 Timişoara, Romania
| | - Dan Gaiță
- Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 49 No., C. D. Loga Bv., 300041 Timişoara, Romania; (A.A.); (D.G.)
- Advanced Research Center of the Institute for Cardiovascular Diseases, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Aniko Manea
- Department of Obstetrics and Gynecology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania;
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16
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Abstract
We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and then showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c. The link to LDL-C was subsequently validated and clarified by the identification of a miR1908-5p-TGFB-LDLR regulatory axis. Here, we continue our investigations on miR1908-5p function by leveraging human primary hepatocytes and HuH-7 hepatoma models. Expression of miR1908-5p was shown to be sensitive to glucose and agents affecting glucose metabolism. Transcriptome-wide changes in primary hepatocytes and HuH-7 cells treated with a miR1908-5p mimic were investigated by enrichment approaches to identify targeted transcripts and cognate pathways. Significant pathways included autophagy and increased mitochondrial function. Reduced activation and/or levels of several key energy and metabolic regulators (AKT, mTOR, ME1, G6PD, AMPK and LKB) were subsequently confirmed in mimic treated HuH-7 cells. These effects were associated with reduced NADPH to NADP+ ratio in HuH-7 cells. LKB1 was validated as a direct target of miR1908-5p, the reintroduction of which was however insufficient to compensate for the impact of the miR1908-5p mimic on AMPK and ACC1. These findings implicate miR1908-5p in metabolic and energy regulation in hepatocyte models via multiple, independent, pathways.
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17
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Mamdouh AM, Khodeer DM, Tantawy MA, Moustafa YM. In-vitro and in-vivo investigation of amygdalin, metformin, and combination of both against doxorubicin on hepatocellular carcinoma. Life Sci 2021; 285:119961. [PMID: 34536497 DOI: 10.1016/j.lfs.2021.119961] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 12/27/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) is a potentially life-threatening cancer. In the current study, anti-HCC efficacy of amygdalin, or metformin alone or in combination in comparison to doxorubicin was studied. MAIN METHODS Both in-vitro and in-vivo based models. HepG-2 and Huh-7 cell lines as established in-vitro model for HCC were treated with different concentrations of indicated drugs to evaluate the cytotoxicity and determine IC50 for 24, 48 and 72 h. Moreover, the effect of different treatments on apoptosis and cell cycle using flow cytometric analysis were studied. Hepatocellular carcinoma induced in rats by diethyl-nitrosamine and carbon tetrachloride was established, to further investigate the efficacy of indicated drugs. Aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were measured by spectrophotometer, alpha-fetoprotein, cytochrome-c, caspase-3 and malondialdehyde were measured by ELISA, and liver biopsies were also evaluated histopathologically. KEY FINDINGS In-vitro results showed that the combination has a promising effect when compared to amygdalin or metformin alone as it is more cytotoxic and have higher ability for induction of apoptosis and arresting cell cycle. In-vivo doxorubicin has a good effect for treating HCC. Also, the combination showed a promising prognostic effect depending on the cytotoxic activity and tumor marker when compared to amygdalin or metformin alone. SIGNIFICANCE Based on the current data, it was hypothesized that amygdalin and metformin especially when used in combination will be a promising approach with low side effects for enhancement of HCC.
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Affiliation(s)
- Ahmed M Mamdouh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Horus University - Egypt, New Damietta 34518, Egypt
| | - Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
| | - Mohamed A Tantawy
- Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Faculty of Pharmacy, BUC, Cairo, Egypt
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18
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Xu Q, Wang Y, Li X, Du Y, Li Y, Zhu J, Lin Y. miR-10a-5p Inhibits the Differentiation of Goat Intramuscular Preadipocytes by Targeting KLF8 in Goats. Front Mol Biosci 2021; 8:700078. [PMID: 34490349 PMCID: PMC8418121 DOI: 10.3389/fmolb.2021.700078] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/13/2021] [Indexed: 11/13/2022] Open
Abstract
Intramuscular fat contributes to the improvement of meat quality of goats. MicroRNAs (miRNAs) have been reported to regulate adipocyte differentiation and maturation. The aim of our study was to clarify whether miR-10a-5p regulates goat intramuscular preadipocyte (GIPC) differentiation and its direct downstream signaling pathway. GIPCs were isolated from longissimus dorsi, whose miR-10a-5p level was measured at different time point of differentiation induction. Adipogenic differentiation of the GIPCs was evaluated by Oil Red O and BODIPY staining, and the expression changes of adipogenic genes like ACC, ATGL, CEBPβ, PPARγ, etc. Related mechanisms were verified by qPCR, a bioinformatic analysis, a dual-luciferase reporter assay, overexpression, and siRNA transfection. Oil Red O and BODIPY staining both with adipogenic gene detection showed that miR-10a-5p suppressed the accumulation of lipid droplets in GIPCs and inhibited its differentiation. The dual-luciferase reporter assay experiment revealed that miR-10a-5p regulates GIPC differentiation by directly binding to KLF8 3’UTR to regulate its expression. Thus, the results indicated that miR-10a-5p inhibits GIPC differentiation by targeting KLF8 and supply a new target for fat deposition and meat quality improvement.
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Affiliation(s)
- Qing Xu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Xin Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Yu Du
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
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Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea. Clin Transl Gastroenterol 2021; 11:e00254. [PMID: 33105165 PMCID: PMC7587422 DOI: 10.14309/ctg.0000000000000254] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797-0.887), colon cancer (HR: 0.865, 95% CI: 0.822-0.91), and liver cancer (HR: 0.709, 95% CI: 0.675-0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209-1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.
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20
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Harati R, Vandamme M, Blanchet B, Bardin C, Praz F, Hamoudi RA, Desbois-Mouthon C. Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells. Mol Pharmacol 2021; 100:32-45. [PMID: 33990407 DOI: 10.1124/molpharm.120.000223] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/09/2021] [Indexed: 01/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.
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Affiliation(s)
- Rania Harati
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Marc Vandamme
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Benoit Blanchet
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christophe Bardin
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Françoise Praz
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Rifat Akram Hamoudi
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christèle Desbois-Mouthon
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
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Anticancer potential of metformin: focusing on gastrointestinal cancers. Cancer Chemother Pharmacol 2021; 87:587-598. [PMID: 33744985 DOI: 10.1007/s00280-021-04256-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 03/08/2021] [Indexed: 12/15/2022]
Abstract
Gastrointestinal cancers are one of the most common types of cancer that have high annual mortality; therefore, identification and introduction of safe drugs in the control and prevention of these cancers are of particular importance. Metformin, a lipophilic biguanide, is the most commonly prescribed agent for type 2 diabetes management. In addition to its great effects on lowering the blood glucose concentrations, the anti-cancer properties of this drug have been reported in many types of cancers such as gastrointestinal cancers. Hence the effects of this agent as a safe drug on the reduction of gastrointestinal cancer risk and suppression of these types of cancers have been studied in different clinical trials. Furthermore, the proposed mechanisms of metformin in preventing the growth of these cancers have been investigated in several studies. In this review, we discuss recent advances in elucidating the molecular mechanisms that are relevant for metformin use in gastrointestinal cancer treatment.
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Ren Y, Luo H. Metformin: The next angiogenesis panacea? SAGE Open Med 2021; 9:20503121211001641. [PMID: 33796300 PMCID: PMC7970164 DOI: 10.1177/20503121211001641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/17/2021] [Indexed: 12/18/2022] Open
Abstract
Angiogenesis, the development of new blood vessels from existing ones, is
a critical process in wound healing and skeletal muscle hypertrophy.
It also leads to pathological conditions such as retinopathy and tumor
genesis. Metformin, the first-line treatment for type 2 diabetic
mellitus, has a specific regulatory effect on the process of
angiogenesis. Anti-angiogenesis can inhibit the occurrence and
metastasis of tumors and alleviate patients’ symptoms with polycystic
ovary syndrome. Moreover, promoting angiogenesis effect can accelerate
wound healing and promote stroke recovery and limb ischemia
reconstruction. This review reorganizes metformin in angiogenesis, and
the underlying mechanism in alleviating disease to bring some
inspiration to relevant researchers.
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Affiliation(s)
- Yu Ren
- Department of Pharmacy, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Hua Luo
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
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Shi T, Kobara H, Oura K, Masaki T. Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. J Hepatocell Carcinoma 2021; 8:45-55. [PMID: 33604315 PMCID: PMC7886236 DOI: 10.2147/jhc.s274933] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths from solid tumors worldwide. The incidence of type 2 diabetes mellitus (T2DM) has increased worldwide in conjunction with the expansion of the Western lifestyle. Furthermore, patients with T2DM have been documented to have an increased risk of HCC, as well as bile tract cancer. Growing evidence shows that T2DM is a strong additive metabolic risk factor for HCC, but how diabetes affects the incidence of HCC requires additional investigation. In this review, we discuss the underlying mechanisms of HCC in patients with T2DM. Topics covered include abnormal glucose and lipid metabolism, hyperinsulinemia, and insulin resistance; the effect of activated platelets; hub gene expression associated with HCC; inflammation and signaling pathways; miRNAs; altered gut microbiota and immunomodulation. The evidence suggests that reducing obesity, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis through efficient measures of prevention may lead to decreased rates of T2DM-related HCC.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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25
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Anti-diabetic drug metformin inhibits cell proliferation and tumor growth in gallbladder cancer via G0/G1 cell cycle arrest. Anticancer Drugs 2021; 31:231-240. [PMID: 31815765 DOI: 10.1097/cad.0000000000000870] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gallbladder cancer is the most common biliary tract cancer with poor prognosis and wide variation in incidence rates worldwide, being very high in some countries in Latin America and Asia. Treatment of type 2 diabetes with metformin causes a reduction in the incidence of cancer. Till date, there are no reports on the anti-tumor effects of metformin in gall bladder cancer. Therefore, this study evaluated the effects of metformin on the proliferation of human gallbladder adenocarcinoma cells in vitro and in vivo, as well as explored the microRNAs associated with the anti-tumor effects of metformin. Metformin inhibited the proliferation in gallbladder adenocarcinoma cell lines NOZ, TGBC14TKB, and TGBC24TKB, and blocked the G0 to G1 transition in the cell cycle. This was accompanied by strong reduction in the expression of G1 cyclins, especially cyclin D1 and its catalytic subunits including cyclin-dependent kinase 4, and in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of receptor tyrosine kinases, especially Tie-2, ALK, PYK, EphA4, and EphA10, as well as angiogenesis-related proteins, including RANTES, TGF-β, and TIMP-1. Moreover, metformin also markedly altered microRNA expression profile leading to an anti-tumor effect. Treatment of athymic nude mice bearing xenograft tumors with metformin inhibited tumor growth. These results suggest that metformin may be used clinically for the treatment of gallbladder adenocarcinoma.
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Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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27
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Ma Y, Zhu Q, Liang J, Li Y, Li M, Zhang Y, Wang X, Zeng Y, Jiao Y. A CRISPR knockout negative screen reveals synergy between CDKs inhibitor and metformin in the treatment of human cancer in vitro and in vivo. Signal Transduct Target Ther 2020; 5:152. [PMID: 32811807 PMCID: PMC7434905 DOI: 10.1038/s41392-020-0203-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/13/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023] Open
Abstract
Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent. However, the lack of a clear understanding of the indications of metformin limits its efficacy. Here, we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment (T18) compared to those of the untreated cells at day 0 (T0) yielded candidate genes. Knockdown of a group of cyclin-dependent kinases (CDKs), including CDK1, CDK4, and CDK6, confirmed the results of the screen. Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo. Although cell cycle parameters were not further altered under the combination treatment, investigation of the metabolome revealed significant changes in cell metabolism, especially with regard to fatty acid oxidation, the tricarboxylic acid cycle and aspartate metabolism. Such changes appeared to be mediated through inhibition of the mTOR pathway. Collectively, our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.
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Affiliation(s)
- Yarui Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Qing Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Junbo Liang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, 10005, Beijing, China
| | - Yifei Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Mo Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Ying Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xiaobing Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. .,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Yixin Zeng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. .,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Yuchen Jiao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. .,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. .,Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
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Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: A review of the current evidence. Life Sci 2020; 254:117717. [PMID: 32339541 DOI: 10.1016/j.lfs.2020.117717] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023]
Abstract
Metformin, a US Food and Drug Administration-approved "star" drug used for diabetes mellitus type 2, has become a topic of increasing interest to researchers due to its anti-neoplastic effects. Growing evidence has demonstrated that metformin may be a promising chemotherapeutic agent, and several clinical trials of metformin use in cancer treatment are ongoing. However, the anti-neoplastic effects of metformin and its underlying mechanisms have not been fully elucidated. In this review, we present the newest findings on the anticancer activities of metformin, and highlight its diverse anticancer mechanisms. Several clinical trials, as well as the limitations of the current evidence are also demonstrated. This review explores the crucial roles of metformin and provides supporting evidence for the repurposing of metformin as a treatment of cancer.
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Affiliation(s)
- Bin Zhao
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jie Luo
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Tongyao Yu
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Liangfu Zhou
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Huanhuan Lv
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Peng Shang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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Regorafenib and ginsenoside combination therapy: inhibition of HepG2 cell growth through modulating survivin and caspase-3 gene expression. Clin Transl Oncol 2020; 22:1491-1498. [PMID: 31965535 DOI: 10.1007/s12094-019-02283-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 12/26/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND This work aimed to investigate the inhibitory effect of regorafenib in combination with ginsenoside on the growth of HepG2 liver cancer cells. METHODS HepG2 liver cancer cells were divided into blank control group, regorafenib single-drug group, ginsenoside single-drug group, and regorafenib/ginsenoside combination group. Cells in the regorafenib single-drug group were treated with regorafenib at 0.25 mg/L, 0.5 mg/L, and 1 mg/L, respectively, while cells in the ginsenoside single-drug group were treated with ginsenoside at 5.0 mg/L, 10.0 mg/L, and 20.0 mg/L, respectively. HepG2 cell proliferation, expression of survivin mRNA, and the apoptotic effector caspase-3 in HepG2 liver cancer cells were assessed. RESULTS An inhibitory effect on the growth of HepG2 liver cancer cells was observed for both the single-drug therapies and the combination therapy. The synergistic inhibitory effect presented by the combination therapy was dependent on the gradient concentration and treatment time. RT-qPCR results showed that both regorafenib and ginsenoside significantly reduced the expression of survivin mRNA in HepG2 liver cancer cells and the expression level of survivin mRNA in the regorafenib/ginsenoside combination group was much lower than those in the regorafenib single-drug group and ginsenoside single-drug group. The two drugs demonstrated synergistic inhibitory effect when used in combination. CONCLUSIONS The findings in this study offered a theoretical insight into clinical use of regorafenib and ginsenoside for treatment of liver cancer.
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Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer. Br J Cancer 2019; 122:233-244. [PMID: 31819186 PMCID: PMC7052204 DOI: 10.1038/s41416-019-0659-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/17/2022] Open
Abstract
Background Metabolic alterations can serve as targets for diagnosis and cancer therapy. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation. Methods We applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterise metabolic reprogramming in murine liver cancer. Results We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to assess their maximal velocity values. Model simulations predicted tumour-specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumour cell killing. Conclusions Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer. We propose that modelling proteomics data from human HCC with our approach will enable an individualised metabolic profiling of tumours and predictions of the efficacy of drug therapies targeting specific metabolic pathways.
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Albini A, Bassani B, Baci D, Dallaglio K, Gallazzi M, Corradino P, Bruno A, Noonan DM. Nutraceuticals and "Repurposed" Drugs of Phytochemical Origin in Prevention and Interception of Chronic Degenerative Diseases and Cancer. Curr Med Chem 2019; 26:973-987. [PMID: 28933290 DOI: 10.2174/0929867324666170920144130] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 08/08/2017] [Accepted: 08/08/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy. OBJECTIVES The validation of novel (chemo)preventive and interceptive approaches, and the use of new or repurposed agents, alone or in combination with registered drugs, are urgently required. RESULTS Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, nonsteroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing antiangiogenic and anti-anti-inflammatory proprieties. Many of them target AMPK and metabolic pathways such as the mTOR axis. We summarize the beneficial effects of several compounds in conferring protection and supporting therapy, and as a paradigm, we present data on terpenoids & biquanides on beer hop xanthohumol and hydroxytryrosol from olive mill waste waters. CONCLUSIONS These molecules could be employed for combinatorial chemoprevention and interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases.
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Affiliation(s)
- Adriana Albini
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy
| | - Barbara Bassani
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy
| | - Denisa Baci
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy
| | - Katiuscia Dallaglio
- Laboratory of Translational Research, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Matteo Gallazzi
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy.,Department of Biotechnologies and Life Sciences, University of Insubria, Varese, Italy
| | - Paola Corradino
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy
| | - Antonino Bruno
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy
| | - Douglas M Noonan
- Scientific and Technology Park, IRCCS MultiMedica, Milano, Italy.,Department of Biotechnologies and Life Sciences, University of Insubria, Varese, Italy
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32
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Jiang X, Tan HY, Teng S, Chan YT, Wang D, Wang N. The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:647. [PMID: 31083406 PMCID: PMC6562911 DOI: 10.3390/cancers11050647] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy.
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Affiliation(s)
- Xue Jiang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Hor-Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Shanshan Teng
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
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Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, Favre C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep 2019; 9:2815. [PMID: 30809021 PMCID: PMC6391381 DOI: 10.1038/s41598-019-39556-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 01/17/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly metastatic cancer with very poor prognosis. AMP activated kinase (AMPK) constitutes a candidate to inhibit HCC progression. First, AMPK is downregulated in HCC. Second, glucose starvation induces apoptosis in HCC cells via AMPK. Correspondingly, metformin activates AMPK and inhibits HCC cell proliferation. Nevertheless, the effect of AMPK activation on HCC cell invasiveness remains elusive. Here, migration/invasion was studied in HCC cells exposed to metformin and glucose starvation. Cell viability, proliferation and differentiation, as well as AMPK and PKA activation were analyzed. In addition, invasiveness in mutants of the AMPKα activation loop was assessed. Metformin decreased cell migration, invasion and epithelial-mesenchymal transition, and interference with AMPKα expression avoided metformin actions. Those antitumor effects were potentiated by glucose deprivation. Metformin activated AMPK at the same time that inhibited PKA, and both effects were enhanced by glucose starvation. Given that AMPKα(S173) phosphorylation by PKA decreases AMPK activation, we hypothesized that the reduction of PKA inhibitory effect by metformin could explain the increased antitumor effects observed. Supporting this, in AMPK activating conditions, cell migration/invasion was further impaired in AMPKα(S173C) mutant cells. Metformin emerges as a strong inhibitor of migration/invasion in HCC cells, and glucose restriction potentiates this effect.
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Affiliation(s)
- Anabela C Ferretti
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Florencia Hidalgo
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Facundo M Tonucci
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Evangelina Almada
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Alejandro Pariani
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - María C Larocca
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Cristián Favre
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
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Zhang C, Hu J, Sheng L, Yuan M, Wu Y, Chen L, Zheng G, Qiu Z. Metformin delays AKT/c-Met-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and ATP generation. Toxicol Appl Pharmacol 2019; 365:51-60. [PMID: 30625338 DOI: 10.1016/j.taap.2019.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/03/2019] [Accepted: 01/04/2019] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.
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Affiliation(s)
- Cong Zhang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Junjie Hu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Lei Sheng
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Ming Yuan
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Yong Wu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Liang Chen
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Guohua Zheng
- Key Laboratory of Chinese Medicine Resource and Compound Prescription, Ministry of Education, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
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35
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Vacante F, Senesi P, Montesano A, Paini S, Luzi L, Terruzzi I. Metformin Counteracts HCC Progression and Metastasis Enhancing KLF6/p21 Expression and Downregulating the IGF Axis. Int J Endocrinol 2019; 2019:7570146. [PMID: 30774659 PMCID: PMC6350585 DOI: 10.1155/2019/7570146] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 09/21/2018] [Accepted: 10/30/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is the common tumor of the liver. Unfortunately, most HCC seem to be resistant to conventional chemotherapy and radiotherapy. The poor efficacy of antitumor agents is also due, at least in part, to the inefficient drug delivery and metabolism exerted by the steatotic/cirrhotic liver that hosts the tumor. Thus, novel approaches in chemotherapy may be needed to improve the survival rate in patients with HCC. Metformin (METF) has been found to lower HCC risk; however, the mechanisms by which METF performs its anticancer activity are not completely elucidated. Previous studies have showed METF action on growth inhibition in the liver in a dose/time-dependent manner and its antitumor role by targeting multiple pathways. We investigated molecular effects of METF in an in vitro human hepatoma model (HepG2), studying cell cycle regulators, tumorigenesis markers, and insulin-like growth factor (IGF) axis regulation. MATERIALS AND METHODS HepG2 cells were treated with METF (400 μM) for 24, 48, and 72 hours. METF action on cell cycle progression and cellular pathways involved in metabolism regulation was evaluated by gene expression analysis, immunofluorescence, and Western blot assay. RESULTS By assessing HepG2 cell viability, METF significantly decreased growth cell capacity raising KLF6/p21 protein content. Moreover, METF ameliorated the cancer microenvironment reducing cellular lipid drop accumulation and promoting AMPK activity. The overexpression of IGF-II molecule and the IGF-I receptor that plays a main role in HCC progression was counteracted by METF. Furthermore, the protein content of HCC principal tumor markers, CK19 and OPN, linked to the metastasis process was significantly reduced by METF stimulus. CONCLUSION Our data show that METF could suppress HepG2 proliferation, through induction of cell cycle arrest at the G0/G1 phase. In addition, METF effect on the cancer microenvironment and on the IGF axis leads to the development of new METF therapeutic use in HCC treatment.
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Affiliation(s)
- Fernanda Vacante
- Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Pamela Senesi
- Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Anna Montesano
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Stefano Paini
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Livio Luzi
- Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Ileana Terruzzi
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
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Zhou J, Han S, Qian W, Gu Y, Li X, Yang K. Metformin induces miR-378 to downregulate the CDK1, leading to suppression of cell proliferation in hepatocellular carcinoma. Onco Targets Ther 2018; 11:4451-4459. [PMID: 30104887 PMCID: PMC6074828 DOI: 10.2147/ott.s167614] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
UNLABELLED Metformin is one of the extensively and most commonly used oral antihyperglycemic agents, but it has been shown to exert antineoplastic effects in many cancer cells. Recent studies have confirmed that metformin has an antitumor effect on hepatocellular carcinoma (HCC). However, the molecular mechanism underlying this effect needs to be further studied. MATERIALS AND METHODS CDK1 and miR-378 expression was analyzed by western blotting and real-time PCR assays. We confirmed the association between miR-378 and CDK1 by dual luciferase reporter assay. The role of the miR-378/CDK1 pathway in proliferation, cell cycle and apoptosis was examined in vitro. The effect of miR-378 on HCC tumor growth was evaluated in nude xenograft mouse model. RESULTS Our study found that metformin significantly inhibited the HCC cell proliferation via inducing G2/M arrest. At the same time, metformin efficiently decreased CDK1 expression and elevated miR-378 level. Moreover, the upregulation of miR-378 also repressed HCC cell proliferation by causing G2/M arrest and inhibited tumor growth. Additionally, we demonstrated that miR-378 directly targeted CDK1 3'UTR and downregulated CDK1 mRNA and protein levels. Furthermore, metformin treatment could not decrease CDK1 expression, suppress HCC cell proliferation, and induce G2/M cell cycle arrest. DISCUSSION Metformin-suppressed HCC cell proliferation was dependent on the inhibitory effect of miR-378 on CDK1 expression. Taken together, we concluded that metformin inhibited HCC cell proliferation via modulating miR-378/CDK1 axis. CONCLUSION Collectively, the current results provide the first evidence, to our knowledge, that miR-378/CDK1 axis is involved in metformin modulating the proliferation of HCC cells, which suggests a novel molecular mechanism underlying the thera peutic effect of metformin on HCC.
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Affiliation(s)
- Jin Zhou
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China,
| | - Sheng Han
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China,
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Science, Beijing, China,
| | - Weichun Qian
- Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yuanyuan Gu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China,
| | - Xiangcheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China,
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Science, Beijing, China,
| | - Kunxing Yang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China,
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Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS. Epigenetic effects of metformin: From molecular mechanisms to clinical implications. Diabetes Obes Metab 2018; 20:1553-1562. [PMID: 29457866 DOI: 10.1111/dom.13262] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 12/15/2022]
Abstract
There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.
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Affiliation(s)
- Stephanie Claire Bridgeman
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Gaewyn Colleen Ellison
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Phillip Edward Melton
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Science, The University of Western Australia, Perth, Western Australia, Australia
| | - Philip Newsholme
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Cyril Desire Sylvain Mamotte
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
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Rastegar M, Marjani HA, Yazdani Y, Shahbazi M, Golalipour M, Farazmandfar T. Investigating Effect of Rapamycin and Metformin on Angiogenesis in Hepatocellular Carcinoma Cell Line. Adv Pharm Bull 2018; 8:63-68. [PMID: 29670840 PMCID: PMC5899784 DOI: 10.15171/apb.2018.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 02/08/2018] [Accepted: 02/10/2018] [Indexed: 12/12/2022] Open
Abstract
Purpose: Human hepatocellular carcinoma is one of the most common causes of death in the world. Metformin and rapamycin may decrease the expression of VEGF protein and subsequently angiogenesis. The purpose of this study was to evaluate the effect of these two drugs on expression of VEGF protein and the cell proliferation in the hepatocellular carcinoma cell line (ATCC HB-8065). Methods: HepG2 was cultured in RPMI-1640 medium at 37°C for 48h as a pre-culture and then treated by different concentrations of metformin (0, 5, 10 and 20 mM) and rapamycin (0, 5, 10 and 20 nM) at different times (12, 24 and 48 h). Cell viability was assessed by the MTT assay. Total RNA was extracted by the Trizol reagent and VEGF gene expression was analyzed by quantitative real-time PCR and was calculated by 2–ΔCt method. The VEGF protein level was determined by Elisa assay. Finally, Apoptosis index was calculated by DAPI staining. Results: Metformin and rapamycin significantly decrease cancer cells viability (p<0.05). Rapamycin but not metformin decreases VEGF gene expression in HepG2 cells. Metformin and rapamycin significantly induce cell apoptosis in hepatocellular carcinoma (HCC) cells. Conclusion: Metformin and rapamycin have an anti-tumor effect on HCC. According to our data rapamycin might have an anti-angiogenesis effect via inhibition of VEGF expression. Our results provide an insight into future clinical strategies to improve chemotherapy outcomes in HCC.
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Affiliation(s)
- Mandana Rastegar
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Haji-Amin Marjani
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Yaghoub Yazdani
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Masoud Golalipour
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Touraj Farazmandfar
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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Choi J, Kim KJ, Koh EJ, Lee BY. Gelidium elegans Extract Ameliorates Type 2 Diabetes via Regulation of MAPK and PI3K/Akt Signaling. Nutrients 2018; 10:E51. [PMID: 29316644 PMCID: PMC5793279 DOI: 10.3390/nu10010051] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/29/2017] [Accepted: 01/05/2018] [Indexed: 12/15/2022] Open
Abstract
Gelidium elegans, a red alga native to the Asia Pacific region, contains biologically active polyphenols. We conducted a molecular biological study of the anti-diabetic effect of Gelidium elegans extract (GEE) in C57BL/KsJ-db/db mice. Mice that had been administered GEE had significantly lower body mass, water consumption, and fasting blood glucose than db/db controls. Moreover, hemoglobin A1c (HbA1c), an indicator of the glycemic status of people with diabetes, was significantly lower in mice that had been administered GEE. We also found that 200 mg/kg/day GEE upregulates the insulin signaling pathway by activating insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K), and increasing the expression of glucose transporter type 4 (GLUT4). In parallel, mitogen-activated protein kinase (MAPK) activity was lower in GEE-treated groups. In summary, these findings indicate that GEE regulates glucose metabolism by activating the insulin signaling pathway and downregulating the MAPK signaling pathway.
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Affiliation(s)
- Jia Choi
- Department of Food Science and Biotechnology, College of Life Science, CHA University, 463-400 Seongnam, Kyonggi, Korea.
| | - Kui-Jin Kim
- Department of Food Science and Biotechnology, College of Life Science, CHA University, 463-400 Seongnam, Kyonggi, Korea.
| | - Eun-Jeong Koh
- Department of Food Science and Biotechnology, College of Life Science, CHA University, 463-400 Seongnam, Kyonggi, Korea.
| | - Boo-Yong Lee
- Department of Food Science and Biotechnology, College of Life Science, CHA University, 463-400 Seongnam, Kyonggi, Korea.
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Metformin synergistically enhances antitumor activity of cisplatin in gallbladder cancer via the PI3K/AKT/ERK pathway. Cytotechnology 2017; 70:439-448. [PMID: 29110119 DOI: 10.1007/s10616-017-0160-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 10/26/2017] [Indexed: 12/11/2022] Open
Abstract
Metformin (Met) is a widely used antidiabetic drug and has demonstrated interesting anticancer effects in various cancer models, alone or in combination with chemotherapeutic drugs. The aim of the present study is to investigate the synergistic effect of Met with cisplatin (Cis) on the tumor growth inhibition of gallbladder cancer cells (GBC-SD and SGC-996) and explore the underlying mechanism. Cells were treated with Met and/or Cis and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that Met and Cis inhibited the proliferation of gallbladder cancer cells, and combination treatment with Met and Cis resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with Met and Cis caused G0/G1 phase arrest by upregulating P21, P27 and downregulating CyclinD1, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, and p-ERK. In addition, pretreatment with a specific AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Met + Cis, suggesting the key role of AKT in this process. More importantly, in nude mice model, Met and Cis in combination displayed more efficient inhibition of tumor weight and volume in the SGC-996 xenograft mouse model than Met or Cis alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which is consistent with our in vitro results. In conclusion, our findings indicate that the combination therapy with Met and Cis exerted synergistic antitumor effects in gallbladder cancer cells through PI3K/AKT/ERK pathway, and combination treatment with Met and Cis would be a promising therapeutic strategy for gallbladder cancer patients.
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Tadokoro T, Morishita A, Sakamoto T, Fujihara S, Fujita K, Mimura S, Oura K, Nomura T, Tani J, Yoneyama H, Iwama H, Himoto T, Niki T, Hirashima M, Masaki T. Galectin‑9 ameliorates fulminant liver injury. Mol Med Rep 2017; 16:36-42. [PMID: 28534962 PMCID: PMC5482106 DOI: 10.3892/mmr.2017.6606] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 03/16/2017] [Indexed: 01/21/2023] Open
Abstract
Fulminant hepatitis is a severe liver disease resulting in hepatocyte necrosis. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has been evaluated as a potential therapeutic agent for various diseases that regulate the host immune system. Concanavalin A (ConA) injection into mice results in serious, immune-mediated liver injury similar to human viral, autoimmune and fulminant hepatitis. The present study investigated the effects of Gal-9 treatment on fulminant hepatitis in vivo and the effect on the expression of microRNAs (miRNAs), in order to identify specific miRNAs associated with the immune effects of Gal-9. A ConA-induced mouse hepatitis model was used to investigate the effects of Gal-9 treatment on overall survival rates, liver enzymes, histopathology and miRNA expression levels. Histological analyses, TUNEL assay, immunohistochemistry and miRNA expression characterization, were used to investigate the degree of necrosis, fibrosis, apoptosis and infiltration of neutrophils and macrophages. Overall survival rates following ConA administration were significantly higher in Gal-9-treated mice compared with control mice treated with ConA + PBS. Histological examination revealed that Gal-9 attenuated hepatocellular damage, reduced local neutrophil infiltration and prevented the local accumulation of macrophages and liver cell apoptosis in ConA-treated mice. In addition, various miRNAs induced by Gal-9 may contribute to its anti-apoptotic, anti-inflammatory and pro-proliferative effects on hepatocytes. The results of the present study demonstrate that Gal-9 may be a candidate therapeutic target for the treatment of fulminant hepatitis.
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Affiliation(s)
- Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa 761‑0123, Japan
| | - Toshiro Niki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Mitsuomi Hirashima
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761‑0793, Japan
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Chiyo T, Kato K, Iwama H, Fujihara S, Fujita K, Tadokoro T, Ohura K, Samukawa E, Yamana Y, Kobayashi N, Matsunaga T, Nishiyama N, Ayaki M, Yachida T, Morishita A, Kobara H, Mori H, Masaki T. Therapeutic potential of the antidiabetic drug metformin in small bowel adenocarcinoma. Int J Oncol 2017; 50:2145-2153. [DOI: 10.3892/ijo.2017.3971] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/15/2017] [Indexed: 11/06/2022] Open
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Ye YQ, Zhang L, Xie J, Zhu HY, Xie Y, Zeng B. Role of VEGF in metformin induced apoptosis of HepG2 cells. Shijie Huaren Xiaohua Zazhi 2017; 25:966-973. [DOI: 10.11569/wcjd.v25.i11.966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the molecular mechanism of metformin induced apoptosis of HepG2 cells.
METHODS HepG2 cells were treated with different concentrations (0-20 mmol/L) of metformin (MET) for 24 h or 10 mmol/L MET for different times (0-48 h), and the effect of MET on cell proliferation was measured by MTT assay. Annexin V-FITC/PI flow cytometry was used to determine the apoptosis rate. RT-PCR was used to analyze the expression of vascular endothelial growth factor (VEGF) in HepG2 cells treated with MET.
RESULTS MET had an obvious inhibitory effect on HepG2 cell proliferation. After treatment with 0, 5, 10, 15, and 20 mmol/L MET for 24 h, the relative cell viability rates of HepG2 cells were 100%, 80.56% ± 0.72%, 71.06% ± 0.70%, 64.73% ± 0.35%, and 54.73% ± 0.40%, respectively, showing a dose-dependent manner. After treatment with 10 mmol/L MET for 0, 12, 24, 36, and 48 h, the relative cell viability rates of HepG2 cells were 100%, 83.40% ± 0.70%, 69.86% ± 0.45%, 60.40% ± 0.88%, and 50.70% ± 0.45%, respectively, showing a time-dependent manner. Annexin V-FITC/PI flow cytometry revealed that the apoptosis rates of HepG2 cell were increased after treatment with 0, 5, 10, 15, and 20 mmol/L MET for 24 h, and the apoptosis rates were 2.78% ± 0.68%, 9.33% ± 0.22%, 17.13% ± 0.10%, 21.61% ± 0.20%, and 25.26% ± 1.09%, respectively, showing a dose-dependent manner. The apoptosis rates of HepG2 cells were increased after treatment with 10 mmol/L for 0, 12, 24, 36, 48 h, and the apoptosis rates were 2.05% ± 0.04%, 8.10% ± 0.08%, 16.53% ± 0.93%, 20.95% ± 0.16%, and 25.65% ± 0.44%, showing a time-dependent manner. The expression of VEGF decreased after treatment with different concentrations of MET for 24 h or 10 mmol/L MET for different times, showing a dose- and time-dependent manner.
CONCLUSION MET can inhibit HepG2 cell proliferation via inducing apoptosis, which may involve the expression of VEGF.
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Zhou XL, Xue WH, Ding XF, Li LF, Dou MM, Zhang WJ, Lv Z, Fan ZR, Zhao J, Wang LX. Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. Oncotarget 2017; 8:55622-55631. [PMID: 28903449 PMCID: PMC5589688 DOI: 10.18632/oncotarget.16973] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/13/2017] [Indexed: 12/12/2022] Open
Abstract
Objectives The objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM). Methods We systemically searched the following databases for studies published between the databases’ dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis. Results A total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642˜0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC. Conclusions The risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy.
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Affiliation(s)
- Xue-Liang Zhou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wen-Hua Xue
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xian-Fei Ding
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Feng Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Meng-Meng Dou
- Department of Integrated Traditional and Western Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wei-Jie Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhuan Lv
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhi-Rui Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Liu-Xing Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Tsai HH, Lai HY, Chen YC, Li CF, Huang HS, Liu HS, Tsai YS, Wang JM. Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway. Oncotarget 2017; 8:13832-13845. [PMID: 28099155 PMCID: PMC5355142 DOI: 10.18632/oncotarget.14640] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 01/04/2017] [Indexed: 12/19/2022] Open
Abstract
Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPD-regulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.
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Affiliation(s)
- Hsin-Hwa Tsai
- Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan
| | - Hong-Yue Lai
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Yueh-Chiu Chen
- Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Huei-Sheng Huang
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Hsiao-Sheng Liu
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan
| | - Yau-Sheng Tsai
- Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ju-Ming Wang
- Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
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Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis. Clin Sci (Lond) 2016; 131:27-36. [PMID: 27803295 DOI: 10.1042/cs20160438] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/30/2016] [Accepted: 10/29/2016] [Indexed: 02/07/2023]
Abstract
Studies suggest that metformin, widely used for treating Type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma (HCC), metformin may provide antitumoral effects. We evaluated the impact of metformin on tumour growth and visceral fat composition using relevant preclinical models of metabolic syndrome. Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow (SC) diet, 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured HCC slices. Visceral fatty acid composition was analysed by magnetic resonance imaging (MRI). Metformin had a dose-dependent inhibitory effect on cell proliferation and apoptosis in vitro through the deregulation of mTOR/AMPK, AKT and extracellular signal regulated kinase (ERK) signalling pathways. Tumour engraftment rates were higher in HFD mice than SC mice (hepatic: 79% compared with 25%, P=0.02) and FR mice (subcutaneous: 86% compared with 50%, P=0.04). Subcutaneous tumour volume was increased in HFD mice (+64% compared with FR and SC, P=0.03). Metformin significantly decreased subcutaneous tumour growth via cell-cycle block and mammalian target of rapamycin (mTOR) pathway inhibition, and also induced hypoxia and decreased angiogenesis. In ex vivo tumour slices, metformin treatment led to increased necrosis, decreased cyclin D1 and increased carbonic anhydrase-9 (CA-9). Metformin caused qualitative changes in visceral fat composition of HFD mice, with decreased proportions of polyunsaturated fatty acids (14.6% ± 2.3% compared with 17.9% ± 3.0%, P=0.04). The potent antitumoral effects of metformin in multiple preclinical models implicating several molecular mechanisms provide a strong rationale for clinical trials including combination studies in HCC patients.
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Zhu HQ, Ma JB, Song X, Gao HJ, Ma CQ, Chang H, Li HG, Liu FF, Lu J, Zhou X. Metformin potentiates the anticancer activities of gemcitabine and cisplatin against cholangiocarcinoma cells in vitro and in vivo. Oncol Rep 2016; 36:3488-3496. [PMID: 27779693 DOI: 10.3892/or.2016.5187] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 06/14/2016] [Indexed: 12/12/2022] Open
Abstract
Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways. Metformin upregulated the expression of p21Waf1 and p27kip1, and downregulated the expression of cyclin D1, a key protein required for cell cycle progression. The combination of gemcitabine and cisplatin inhibited the proliferation and induced the apoptosis of human cholangiocarcinoma cells by inducing the phosphorylation of AMPK, downregulating cyclin D1, and activating caspase-3. Administration of metformin enhanced the efficacy of gemcitabine and cisplatin to suppress the growth of cholangiocarcinoma tumors established in experimental models by inhibiting cell proliferation and inducing cell apoptosis through their effects on AMPK, cyclin D1 and caspase-3. Given that metformin has been used to treat type 2 diabetes patients for over half a century due to its superior safety profile, the results presented here indicate that metformin may be a potent agent for enhancing the efficacy of gemcitabine and cisplatin in the treatment of cholangiocarcinoma.
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Affiliation(s)
- Hua-Qiang Zhu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jin-Ben Ma
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Xie Song
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Heng-Jun Gao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Chao-Qun Ma
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Hong Chang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Hong-Guang Li
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Fang-Feng Liu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jun Lu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Xu Zhou
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
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Fujita K, Iwama H, Oura K, Tadokoro T, Hirose K, Watanabe M, Sakamoto T, Katsura A, Mimura S, Nomura T, Tani J, Miyoshi H, Morishita A, Yoneyama H, Okano K, Suzuki Y, Himoto T, Masaki T. Metformin-suppressed differentiation of human visceral preadipocytes: Involvement of microRNAs. Int J Mol Med 2016; 38:1135-40. [PMID: 27600587 PMCID: PMC5029962 DOI: 10.3892/ijmm.2016.2729] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 08/31/2016] [Indexed: 12/12/2022] Open
Abstract
Visceral adipose tissue contributes to the pathophysiology of metabolic syndrome. Metformin has been reported to suppress lipogenesis in a murine preadipocyte cell line. However, the effect of metformin on the differentiation of human visceral adipose tissue remains unknown. MicroRNAs (miRNAs or miRs) have been suggested as therapeutic targets because of their involvement in the differentiation and maturation of fatty cells. The aim of this study was to determine whether metformin suppresses the differentiation of human preadipocytes and to identify miRNAs associated with the regulation of lipid metabolism. Human visceral preadipocytes (HPrAD-vis) were preincubated in growth media and then cultured with differentiation media containing metformin for 1 or 2 weeks. Adipogenic differentiation of the cells was assessed by Oil Red O staining, and soluble adiponectin in the culture media was measured using an enzyme-linked immunosorbent assay. Cell proliferation was assessed using a WST-8 assay, and the gene and protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) was determined by RT-qPCR and western blot analysis, respectively. miRNAs were profiled using human miRNA Oligo chips after total RNA was extracted and labeled. Oil Red O staining showed that metformin suppressed the accumulation of lipid droplets in HPrAD-vis cells. The adiponectin concentration in the culture media was also decreased in metformin-treated cells. The WST-8 assay revealed no effect on proliferation or growth inhibition following metformin treatment, although metformin suppressed the expression of PPARγ and C/EBPα. miRNA profiling further revealed differences between the metformin-treated group and control HPrAD-vis cells. Thus, the findings of the present study demonstrated that metformin suppressed the differentiation of human preadipocytes in vitro and altered the miRNA profile of these cells. Thus, the miRNAs whose expression levels were altered by metformin may contribute to the observed suppression of HPrAD-vis cell differentiation.
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Affiliation(s)
- Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kayo Hirose
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Miwako Watanabe
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Akiko Katsura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Masaki T. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6100-13. [PMID: 27468203 PMCID: PMC4945972 DOI: 10.3748/wjg.v22.i27.6100] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
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50
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Sun Y, Tao C, Huang X, He H, Shi H, Zhang Q, Wu H. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. Onco Targets Ther 2016; 9:2845-53. [PMID: 27274280 PMCID: PMC4869652 DOI: 10.2147/ott.s99770] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The antidiabetic drug metformin has been shown to possess antitumor functions in many types of cancers. Although studies have revealed its beneficial effects on the prognosis of hepatocellular carcinoma (HCC), the detailed molecular mechanism underlying this event remains largely unknown. In this work, we showed that miR-23a was significantly induced upon metformin treatment; inhibition of miR-23a abrogated the proapoptotic effect of metformin in HepG2 cells. We next established forkhead box protein A1 (FOXA1) as the functional target of miR-23a, and silencing FOXA1 mimicked the effect of metformin. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of p53 were increased upon metformin treatment, and the inhibition of p53 abrogated the induction of miR-23a by metformin, suggesting that AMPK/p53 signaling axis is responsible for the induction of miR-23a by metformin. In summary, we unraveled a novel AMPK/p53/miR-23a/FOXA1 axis in the regulation of apoptosis in HCC, and the application of metformin could, therefore, be effective in the treatment of HCC.
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Affiliation(s)
- Yunpeng Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chonglin Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xiaming Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Han He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Hongqi Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Huanhuan Wu
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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