Original Communication| Volume 144, ISSUE 3, P374-384, September 2008

Hepatocyte growth factor improves survival after partial hepatectomy in cirrhotic rats suppressing apoptosis of hepatocytes


      Liver failure after hepatic resection is still a critical issue in the treatment of hepatic tumors in patients with liver cirrhosis. In the current study, the effect of hepatocyte growth factor (HGF) gene transfer, which is a multipotent growth factor, was examined in rats with liver cirrhosis that underwent 2/3 partial hepatectomy (PH).


      Rats were treated with 1 mL of 1% dimethylnitrosoamine (DMN) 3 consecutive days per week for 4 weeks and then received a 2/3 PH. Three days before the PH, human HGF gene plasmid (20 μg) encapsulated in hemagglutinating virus of Japan (HVJ)-liposome was administered through a direct injection in the portal vein. Control cirrhotic rats received empty HVJ-liposome in the same manner.


      HGF gene transfer significantly improved survival after PH in the cirrhotic rats, and it stimulated BrdU uptake in hepatocytes. Although the HGF gene transfer did not change the liver regeneration rate after PH, it suppressed hepatocyte apoptosis and upregulated an antiapoptotic protein, Bcl-xl, but it did not affect the expression of Bax, which is a proapoptotic protein.


      HGF gene transfer to cirrhotic livers improves liver failure-associated death after PH upregulating expression of an antiapoptotic protein, Bcl-xl.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Farges O.
        • Malassagne B.
        • Flejou J.F.
        • Balzan S.
        • Sauvanet A.
        • Belghiti J.
        Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal.
        Ann Surg. 1999; 229: 210-215
        • Nagasue N.
        • Kohno H.
        • Tachibana M.
        • Yamanoi A.
        • Ohmori H.
        • El-Assal O.N.
        Prognostic factors after hepatic resection for hepatocellular carcinoma associated with Child-Turcotte class B and C cirrhosis.
        Ann Surg. 1999; 229: 84-90
        • Matsumoto K.
        • Nakamura T.
        Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions.
        Crit Rev Oncog. 1992; 3: 27-54
        • Boros P.
        • Miller C.M.
        Hepatocyte growth factor: a multifunctional cytokine.
        Lancet. 1995; 345: 293-295
        • Ueki T.
        • Kaneda Y.
        • Tsutsui H.
        • Nakanishi K.
        • Sawa Y.
        • Morishita R.
        • et al.
        Hepatocyte growth factor gene therapy of liver cirrhosis in rats.
        Nat Med. 1999; 5: 226-230
        • Kaibori M.
        • Kwon A.H.
        • Nakagawa M.
        • Wei T.
        • Uetsuji S.
        • Kamiyama Y.
        • et al.
        Stimulation of liver regeneration and function after partial hepatectomy in cirrhotic rats by continuous infusion of recombinant human hepatocyte growth factor.
        J Hepatol. 1997; 27: 381-390
        • Xue F.
        • Takahara T.
        • Yata Y.
        • Kuwabara Y.
        • Shinno E.
        • Nonome K.
        • et al.
        Hepatocyte growth factor gene therapy accelerates regeneration in cirrhotic mouse livers after hepatectomy.
        Gut. 2003; 52: 694-700
        • Ozawa S.
        • Uchiyama K.
        • Nakamori M.
        • Ueda K.
        • Iwahashi M.
        • Ueno H.
        • et al.
        Combination gene therapy of HGF and truncated type II TGF-beta receptor for rat liver cirrhosis after partial hepatectomy.
        Surgery. 2006; 139: 563-573
        • Seki T.
        • Hagiya M.
        • Shimonishi M.
        • Nakamura T.
        • Shimizu S.
        Organization of the human hepatocyte growth factor-encoding gene.
        Gene. 1991; 102: 213-219
        • Higgins G.M.
        • Anderson R.M.
        Experimental pathology of liver: restoration of liver of the white rat following partial surgical removal.
        Arch Pathol. 1931; 365: 179-183
        • Wilkinson D.G.
        • Peters G.
        • Dickson C.
        • McMahon A.P.
        Expression of the FGF-related proto-oncogene int-2 during gastrulation and neurulation in the mouse.
        EMBO J. 1988; 7: 691-695
        • Honda S.
        • Kagoshima M.
        • Wanaka A.
        • Tohyama M.
        • Matsumoto K.
        • Nakamura T.
        Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor.
        Brain Res Mol Brain Res. 1995; 32: 197-210
        • D'Errico A.
        • Fiorentino M.
        • Ponzetto A.
        • Daikuhara Y.
        • Tsubouchi H.
        • Brechot C.
        • et al.
        Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does.
        Hepatology. 1996; 24: 60-64
        • Gavrieli Y.
        • Sherman Y.
        • Ben-Sasson S.A.
        Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
        J Cell Biol. 1992; 119: 493-501
        • Iimuro Y.
        • Nishiura T.
        • Hellerbrand C.
        • Behrns K.E.
        • Schoonhoven R.
        • Grisham J.W.
        • et al.
        NFkappaB prevents apoptosis and liver dysfunction during liver regeneration.
        J Clin Invest. 1998; 101: 802-811
        • Sakamoto T.
        • Liu Z.
        • Murase N.
        • Ezure T.
        • Yokomuro S.
        • Poli V.
        • et al.
        Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy.
        Hepatology. 1999; 29: 403-411
        • Tzung S.P.
        • Fausto N.
        • Hockenbery D.M.
        Expression of Bcl-2 family during liver regeneration and identification of Bcl-x as a delayed early response gene.
        Am J Pathol. 1997; 150: 1985-1995
        • Cressman D.E.
        • Greenbaum L.E.
        • Haber B.A.
        • Taub R.
        Rapid activation of post-hepatectomy factor/nuclear factor kappa B in hepatocytes, a primary response in the regenerating liver.
        J Biol Chem. 1994; 269: 30429-30435
        • Taub R.
        Liver regeneration 4: transcriptional control of liver regeneration.
        FASEB J. 1996; 10: 413-427
        • Kren B.T.
        • Trembley J.H.
        • Krajewski S.
        • Behrens T.W.
        • Reed J.C.
        • Steer C.J.
        Modulation of apoptosis-associated genes bcl-2, bcl-x, and bax during rat liver regeneration.
        Cell Growth Differ. 1996; 7: 1633-1642
        • Akcali K.C.
        • Dalgic A.
        • Ucar A.
        • Haj K.B.
        • Guvenc D.
        Expression of bcl-2 gene family during resection induced liver regeneration: comparison between hepatectomized and sham groups.
        World J Gastroenterol. 2004; 10: 279-283
        • Hirano T.
        • Fujimoto J.
        • Ueki T.
        • Yamamoto H.
        • Takeuchi M.
        • Okamoto E.
        • et al.
        HVJ-liposome mediated gene transfer into hepatocytes in vivo.
        J Hepatol. 1998; 29: 910-914
        • Xu B.
        • Broome U.
        • Uzunel M.
        • Nava S.
        • Ge X.
        • Kumagai-Braesch M.
        • et al.
        Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis.
        Am J Pathol. 2003; 163: 1275-1289
        • Hirano T.
        • Fujimoto J.
        • Ueki T.
        • Yamamoto H.
        • Iwasaki T.
        • Morisita R.
        • et al.
        Persistent gene expression in rat liver in vivo by repetitive transfections using HVJ-liposome.
        Gene Ther. 1998; 5: 459-464
        • Kosai K.
        • Matsumoto K.
        • Funakoshi H.
        • Nakamura T.
        Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice.
        Hepatology. 1999; 30: 151-159
        • Li Z.
        • Mizuno S.
        • Nakamura T.
        Antinecrotic and antiapoptotic effects of hepatocyte growth factor on cholestatic hepatitis in a mouse model of bile-obstructive diseases.
        Am J Physiol Gastrointest Liver Physiol. 2007; 292: G639-G646
        • Bardelli A.
        • Longati P.
        • Albero D.
        • Goruppi S.
        • Schneider C.
        • Ponzetto C.
        • et al.
        HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death.
        EMBO J. 1996; 15: 6205-6212