Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
January-2016 Volume 13 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
January-2016 Volume 13 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats

  • Authors:
    • Woori Jo
    • Eun‑Sil Yu
    • Minsun Chang
    • Hyun‑Kyu Park
    • Hyun‑Ji Choi
    • Jae‑Eun Ryu
    • Sungwoong Jang
    • Hyo‑Ju Lee
    • Ja‑June Jang
    • Woo‑Chan Son
  • View Affiliations / Copyright

    Affiliations: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea, Department of Medical and Pharmaceutical Sciences, Sookmyung Woman's University, Seoul 140‑742, Republic of Korea, Department of Pathology, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea
    Copyright: © Jo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 146-152
    |
    Published online on: November 6, 2015
       https://doi.org/10.3892/mmr.2015.4513
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)‑induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma‑specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S‑transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK‑dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high‑risk patients, including chronic hepatitis and cirrhosis.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Bosch FX, Ribes J, Cléries R and Díaz M: Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 9:191–211. 2005. View Article : Google Scholar : PubMed/NCBI

3 

Maronpot RR, Montgomery CA Jr, Boorman GA and McConnell EE: National toxicology program nomenclature for hepatoproliferative lesions of rats. Toxicol Pathol. 14:263–273. 1986. View Article : Google Scholar : PubMed/NCBI

4 

Eustis SL: The sequential development of cancer: A morphological perspective. Toxicol Lett. 49:267–281. 1989. View Article : Google Scholar : PubMed/NCBI

5 

Wild CP and Hall AJ: Primary prevention of hepatocellular carcinoma in developing countries. Mutat Res. 462:381–393. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Ogawa K: Molecular pathology of early stage chemically induced hepatocarcinogenesis. Pathol Int. 59:605–622. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Kirpichnikov D, McFarlane SI and Sowers JR: Metformin: An update. Ann Intern Med. 137:25–33. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Hirsch HA, Iliopoulos D, Tsichlis PN and Struhl K: Metformin selectively targets cancer stem cells and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69:7507–7511. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Aljada A and Mousa SA: Metformin and neoplasia: Implications and indications. Pharmacol Ther. 133:108–115. 2012. View Article : Google Scholar

10 

Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B and Gandini S: Metformin and cancer risk in diabetic patients: A systematic review and meta-analysis. Cancer Prev Res (Phila). 3:1451–1461. 2010. View Article : Google Scholar

11 

Algire C, Zakikhani M, Blouin MJ, Shuai JH and Pollak M: Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 15:833–839. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, Saxena NK, Biswal S and Girnun GD: Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila). 5:544–552. 2012. View Article : Google Scholar

13 

Qu Z, Zhang Y, Liao M, Chen Y, Zhao J and Pan Y: In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma. Hepatol Res. 42:922–933. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Chen HP, Shieh JJ, Chang CC, Chen TT, Lin JT, Wu MS, Lin JH and Wu CY: Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: Population-based and in vitro studies. Gut. 62:606–615. 2013. View Article : Google Scholar

15 

Zheng L, Yang W, Wu F, Wang C, Yu L, Tang L, Qiu B, Li Y, Guo L, Wu M, et al: Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res. 19:5372–5380. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Morimura S, Suzuki T, Hochi S, Yuki A, Nomura K, Kitagawa T, Nagatsu I, Imagawa M and Muramatsu M: Trans-activation of glutathione transferase P gene during chemical hepatocarcinogenesis of the rat. Proc Natl Acad Sci USA. 90:2065–2068. 1993. View Article : Google Scholar : PubMed/NCBI

17 

Saito T, Chiba T, Yuki K, Zen Y, Oshima M, Koide S, Motoyama T, Ogasawara S, Suzuki E, Ooka Y, et al: Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. PLoS One. 8:e700102013. View Article : Google Scholar : PubMed/NCBI

18 

Lowes KN, Croager EJ, Olynyk JK, Abraham LJ and Yeoh GC: Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol. 18:4–12. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Zakikhani M, Dowling R, Fantus IG, Sonenberg N and Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Rocha GZ, Dias MM, Ropelle ER, Osório-Costa F, Rossato FA, Vercesi AE, Saad MJ and Carvalheira JB: Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 17:3993–4005. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Kourelis TV and Siegel RD: Metformin and cancer: New applications for an old drug. Med Oncol. 29:1314–1327. 2012. View Article : Google Scholar

22 

Memmott RM and Dennis PA: LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J Clin Oncol. 27:e226author reply e227. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108:1167–1174. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Zakikhani M, Dowling RJ, Sonenberg N and Pollak MN: The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila). 1:369–375. 2008. View Article : Google Scholar

25 

Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F and Viollet B: Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 120:2355–2369. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, et al: Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11:390–401. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M and Cantley LC: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 310:1642–1646. 2005. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Jo W, Yu ES, Chang M, Park HK, Choi HJ, Ryu JE, Jang S, Lee HJ, Jang JJ, Son WC, Son WC, et al: Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats. Mol Med Rep 13: 146-152, 2016.
APA
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J. ... Son, W. (2016). Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats. Molecular Medicine Reports, 13, 146-152. https://doi.org/10.3892/mmr.2015.4513
MLA
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J., Jang, S., Lee, H., Jang, J., Son, W."Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats". Molecular Medicine Reports 13.1 (2016): 146-152.
Chicago
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J., Jang, S., Lee, H., Jang, J., Son, W."Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats". Molecular Medicine Reports 13, no. 1 (2016): 146-152. https://doi.org/10.3892/mmr.2015.4513
Copy and paste a formatted citation
x
Spandidos Publications style
Jo W, Yu ES, Chang M, Park HK, Choi HJ, Ryu JE, Jang S, Lee HJ, Jang JJ, Son WC, Son WC, et al: Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats. Mol Med Rep 13: 146-152, 2016.
APA
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J. ... Son, W. (2016). Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats. Molecular Medicine Reports, 13, 146-152. https://doi.org/10.3892/mmr.2015.4513
MLA
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J., Jang, S., Lee, H., Jang, J., Son, W."Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats". Molecular Medicine Reports 13.1 (2016): 146-152.
Chicago
Jo, W., Yu, E., Chang, M., Park, H., Choi, H., Ryu, J., Jang, S., Lee, H., Jang, J., Son, W."Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats". Molecular Medicine Reports 13, no. 1 (2016): 146-152. https://doi.org/10.3892/mmr.2015.4513
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team