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Long-term intervention of taurocholic acid over-expressing in cholestatic liver disease inhibits the growth of hepatoma cells
Corresponding Author(s) : Xiujuan Zhang
Cellular and Molecular Biology,
Vol. 66 No. 2: Issue 2
Abstract
Bile acids usually build up in patients with cholestatic liver disease. It was found that the concentration of taurocholic acid (TCA), one of the taurine conjugates of primary bile acids in serum, was elevated the most. While the role played by TCA in the disease is unclear, there is concern whether TCA contributes to the development of hepatocarcinoma from cholestasis. In the present study, the cell viability, flow cytometry, real-time polymerase chain reaction, intracellular ROS measurement, and intracellular Ca2+ measurement were used to investigate the effects of TCA on THLE-2 and HepG2 cells. The results showed that TCA is capable of inhibiting HepG2 cell growth whereas it has relatively little or no impact on that of THLE-2 cells until later stages of 16-day treatment. The growth inhibition is a result of cell apoptosis induced by the increase of Ca2+ and ROS level, and also associated with the increased expression of c-Myc, CEBPα, TNF-α, ICAM-1, VCAM-1, CXCL-2, Egr-1. HepG2 growth inhibition could contribute to the research on the treatment methods of patients already with hepatocarcinoma.
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- Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer Mar 1 2015; 136(5): E359-386.
- Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013/09// 2013; 145(3): 521-536.
- Llovet JM, Zucman-Rossi J, Pikarsky E et al. Hepatocellular carcinoma. Nature Reviews Disease Primers 04/14/online 2016; 2: 16018.
- Verhaag EM, Buist-Homan M, Koehorst M, Groen AK, Moshage H, Faber KN. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity. PLoS One 2016; 11(3): e0149782.
- Xie G, Wang X, Huang F et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. International journal of cancer 06/17 2016; 139(8): 1764-1775.
- Trottier J, Białek A, Caron P et al. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2012/04// 2012; 44(4): 303-310.
- Trottier J, Białek A, Caron P, Straka RJ, Milkiewicz P, Barbier O. Profiling circulating and urinary bile acids in patients with biliary obstruction before and after biliary stenting. PloS one 2011 2011; 6(7): e22094.
- Woolbright BL, McGill MR, Yan H, Jaeschke H. Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes. Basic & clinical pharmacology & toxicology 08/13 2016; 118(2): 160-167.
- Liu ZM, Zhang ZF, Huang M et al. Taurocholic acid is an active promoting factor, not just a biomarker of progression of liver cirrhosis: evidence from a human metabolomic study and in vitro experiments. Bmc Gastroenterology Jul 2018; 18: 9.
- Krause GC, Lima KG, Haute GV et al. Fructose-1,6-bisphosphate decreases IL-8 levels and increases the activity of pro-apoptotic proteins in HepG2 cells. Biomed Pharmacother 2017/05// 2017; 89: 358-365.
- Chen G, Goeddel D. TNF-R1 signaling: A beautiful pathway. 2002; 296: 1634-1635.
- Eilers M, Eisenman RN. Myc's broad reach. Genes Dev 2008/10// 2008; 22(20): 2755-2766.
- Lin CY, Lovén J, Rahl PB et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012/09// 2012; 151(1): 56-67.
- Nie Z, Hu G, Wei G et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012/09// 2012; 151(1): 68-79.
- Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene 2001/09/01 2001; 20(40): 5595-5610.
- Wang H, Iakova P, Wilde M et al. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Molecular cell 2001/10// 2001; 8(4): 817-828.
- Ogura K, Terasaki Y, Miyoshi-Akiyama T et al. Vibrio cholerae Cholix Toxin-Induced HepG2 Cell Death is Enhanced by Tumor Necrosis Factor-Alpha Through ROS and Intracellular Signal-Regulated Kinases. Toxicol Sci Apr 1 2017; 156(2): 455-468.
- Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G, Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. Journal of immunology (Baltimore, Md : 1950) Aug 15 1994; 153(4): 1778-1788.
- Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G, Kouroumalis EA. Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells. World journal of gastroenterology Jan 21 2011; 17(3): 313-321.
- Ding J, Xu K, Zhang J et al. Overexpression of CXCL2 inhibits cell proliferation and promotes apoptosis in hepatocellular carcinoma. BMB Rep Dec 2018; 51(12): 630-635.
- Kong DH, Kim YK, Kim MR, Jang JH, Lee S. Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. International journal of molecular sciences Apr 2 2018; 19(4).
- Yoong KF, Mcnab G, ., Hübscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. Journal of Immunology 1998; 160(8): 3978.
- Ding YB, Chen GY, Xia JG, Zang XW, Yang HY, Yang L. Association of VCAM-1 overexpression with oncogenesis, tumor angiogenesis and metastasis of gastric carcinoma. World J Gastroenterol 2003; 9(7): 1409-1414.
- Bouillon M, Tessier P, Boulianne R, Destrempe R, Audette M. Regulation by retinoic acid of ICAM-1 expression on human tumor cell lines. Biochimica Et Biophysica Acta 1991; 1097(2): 95.
- Liu C, Rangnekar VM, Adamson E, Mercola D. Suppression of growth and transformation and induction of apoptosis by EGR-1. Cancer Gene Ther 1998 Jan-Feb 1998; 5(1): 3-28.
- Ponchel F, Milner J. Temperature sensitivity of human wild-type and mutant p53 proteins expressed in vivo. Br J Cancer 1998/05// 1998; 77(10): 1555-1561.
- Xie B, Wang C, Zheng Z et al. Egr-1 transactivates Bim gene expression to promote neuronal apoptosis. J Neurosci 2011/03// 2011; 31(13): 5032-5044.
- Yu Y, Duan J, Yu Y et al. Silica nanoparticles induce autophagy and autophagic cell death in HepG2 cells triggered by reactive oxygen species. Journal of hazardous materials 2014/04// 2014; 270: 176-186.
- Akhtar MJ, Ahamed M, Kumar S, Khan MM, Ahmad J, Alrokayan SA. Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species. Int J Nanomedicine 2012 2012; 7: 845-857.
- Duan Y, Gross RA, Sheu S-S. Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. The Journal of physiology 2007/12// 2007; 585(Pt 3): 741-758.
- Urushitani M, Nakamizo T, Inoue R et al. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. Journal of neuroscience research Mar 1 2001; 63(5): 377-387.
- Adachi T, Kaminaga T, Yasuda H, Kamiya T, Hara H. The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury. J Clin Biochem Nutr 2014/03// 2014; 54(2): 129-135.
References
Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer Mar 1 2015; 136(5): E359-386.
Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013/09// 2013; 145(3): 521-536.
Llovet JM, Zucman-Rossi J, Pikarsky E et al. Hepatocellular carcinoma. Nature Reviews Disease Primers 04/14/online 2016; 2: 16018.
Verhaag EM, Buist-Homan M, Koehorst M, Groen AK, Moshage H, Faber KN. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity. PLoS One 2016; 11(3): e0149782.
Xie G, Wang X, Huang F et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. International journal of cancer 06/17 2016; 139(8): 1764-1775.
Trottier J, Białek A, Caron P et al. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2012/04// 2012; 44(4): 303-310.
Trottier J, Białek A, Caron P, Straka RJ, Milkiewicz P, Barbier O. Profiling circulating and urinary bile acids in patients with biliary obstruction before and after biliary stenting. PloS one 2011 2011; 6(7): e22094.
Woolbright BL, McGill MR, Yan H, Jaeschke H. Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes. Basic & clinical pharmacology & toxicology 08/13 2016; 118(2): 160-167.
Liu ZM, Zhang ZF, Huang M et al. Taurocholic acid is an active promoting factor, not just a biomarker of progression of liver cirrhosis: evidence from a human metabolomic study and in vitro experiments. Bmc Gastroenterology Jul 2018; 18: 9.
Krause GC, Lima KG, Haute GV et al. Fructose-1,6-bisphosphate decreases IL-8 levels and increases the activity of pro-apoptotic proteins in HepG2 cells. Biomed Pharmacother 2017/05// 2017; 89: 358-365.
Chen G, Goeddel D. TNF-R1 signaling: A beautiful pathway. 2002; 296: 1634-1635.
Eilers M, Eisenman RN. Myc's broad reach. Genes Dev 2008/10// 2008; 22(20): 2755-2766.
Lin CY, Lovén J, Rahl PB et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012/09// 2012; 151(1): 56-67.
Nie Z, Hu G, Wei G et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012/09// 2012; 151(1): 68-79.
Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene 2001/09/01 2001; 20(40): 5595-5610.
Wang H, Iakova P, Wilde M et al. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Molecular cell 2001/10// 2001; 8(4): 817-828.
Ogura K, Terasaki Y, Miyoshi-Akiyama T et al. Vibrio cholerae Cholix Toxin-Induced HepG2 Cell Death is Enhanced by Tumor Necrosis Factor-Alpha Through ROS and Intracellular Signal-Regulated Kinases. Toxicol Sci Apr 1 2017; 156(2): 455-468.
Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G, Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. Journal of immunology (Baltimore, Md : 1950) Aug 15 1994; 153(4): 1778-1788.
Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G, Kouroumalis EA. Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells. World journal of gastroenterology Jan 21 2011; 17(3): 313-321.
Ding J, Xu K, Zhang J et al. Overexpression of CXCL2 inhibits cell proliferation and promotes apoptosis in hepatocellular carcinoma. BMB Rep Dec 2018; 51(12): 630-635.
Kong DH, Kim YK, Kim MR, Jang JH, Lee S. Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. International journal of molecular sciences Apr 2 2018; 19(4).
Yoong KF, Mcnab G, ., Hübscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. Journal of Immunology 1998; 160(8): 3978.
Ding YB, Chen GY, Xia JG, Zang XW, Yang HY, Yang L. Association of VCAM-1 overexpression with oncogenesis, tumor angiogenesis and metastasis of gastric carcinoma. World J Gastroenterol 2003; 9(7): 1409-1414.
Bouillon M, Tessier P, Boulianne R, Destrempe R, Audette M. Regulation by retinoic acid of ICAM-1 expression on human tumor cell lines. Biochimica Et Biophysica Acta 1991; 1097(2): 95.
Liu C, Rangnekar VM, Adamson E, Mercola D. Suppression of growth and transformation and induction of apoptosis by EGR-1. Cancer Gene Ther 1998 Jan-Feb 1998; 5(1): 3-28.
Ponchel F, Milner J. Temperature sensitivity of human wild-type and mutant p53 proteins expressed in vivo. Br J Cancer 1998/05// 1998; 77(10): 1555-1561.
Xie B, Wang C, Zheng Z et al. Egr-1 transactivates Bim gene expression to promote neuronal apoptosis. J Neurosci 2011/03// 2011; 31(13): 5032-5044.
Yu Y, Duan J, Yu Y et al. Silica nanoparticles induce autophagy and autophagic cell death in HepG2 cells triggered by reactive oxygen species. Journal of hazardous materials 2014/04// 2014; 270: 176-186.
Akhtar MJ, Ahamed M, Kumar S, Khan MM, Ahmad J, Alrokayan SA. Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species. Int J Nanomedicine 2012 2012; 7: 845-857.
Duan Y, Gross RA, Sheu S-S. Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. The Journal of physiology 2007/12// 2007; 585(Pt 3): 741-758.
Urushitani M, Nakamizo T, Inoue R et al. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. Journal of neuroscience research Mar 1 2001; 63(5): 377-387.
Adachi T, Kaminaga T, Yasuda H, Kamiya T, Hara H. The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury. J Clin Biochem Nutr 2014/03// 2014; 54(2): 129-135.