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Inhibition of hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) as a mechanism of arsenic carcinogenesis

  • Inorganic Compounds
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Abstract

Inorganic arsenic (i-As) is a naturally occurring toxic metalloid affecting millions of people worldwide. It is known to be carcinogen, liver being a potential target, and related to the prevalence of diabetes in arseniasis-endemic areas. Hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) are key members of a transcriptional network essential for normal liver architecture. Changes in HNF1α and HNF4α expression are clearly associated with the development of liver malignancies and diabetes in humans. In this work, hepatic HepG2 cells and golden Syrian hamsters were exposed to sub-toxic, environmentally relevant doses of sodium arsenite (SA; up to 10 μM in vitro, 15 mg/L in vivo) in order to evaluate whether arsenic is able to compromise the expression of hepatocyte nuclear factors. Also, liver histopathological examination was carried out, and several markers of hepatocyte differentiation and glucose metabolism status were determined as a measure of i-As-induced effects. Results show a consistent down-regulation of HNF1α and HNF4α under a scenario of exposure where HepG2 cells (1) gained resistance to arsenic-induced toxicity/apoptosis, (2) attained loss of tissue-specific features (as shown by the observed down-regulation of ALDOB, PEPCK and CYP1A2, triggering of the epithelial-to-mesenchymal transition program and the hypersecretion of matrix metalloproteinase-2 and 9), (3) failed to maintain balanced expression of the “stemness” genes C-MYC, OCT3/4, LIN28 and NOTCH2 and (4) showed glucose metabolism impairment. We conclude that the i-As-induced down-regulation of HNF1α and HNF4α under chronic settings may play a central role in the features of disease and cancer observed both in vivo and in vitro.

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References

  • Achanzar WE, Brambila EM, Diwan BA, Webber MM, Waalkes MP (2002) Inorganic arsenite-induced malignant transformation of human prostate epithelial cells. J Natl Cancer Inst 94:1888–1891

    Article  PubMed  CAS  Google Scholar 

  • Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119:1438–1449

    Article  PubMed  CAS  Google Scholar 

  • Bluteau O, Jeannot E, Bioulac-Sage P, Marques JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J (2002) Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 32:312–315

    Article  PubMed  CAS  Google Scholar 

  • Bonassi S, Znaor A, Ceppi M, Lando C, Chang WP, Holland N, Kirsch-Volders M, Zeiger E, Ban S, Barale R, Bigatti MP, Bolognesi C, Cebulska-Wasilewska A, Fabianova E, Fucic A, Hagmar L, Joksic G, Martelli A, Migliore L, Mirkova E, Scarfi MR, Zijno A, Norppa H, Fenech M (2007) An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis 28:625–631

    Article  PubMed  CAS  Google Scholar 

  • Chen WS, Manova K, Weinstein DC, Duncan SA, Plump AS, Prezioso VR, Bachvarova RF, Darnell JE Jr (1994) Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev 8:2466–2477

    Article  PubMed  CAS  Google Scholar 

  • Costa RH, Kalinichenko VV, Holterman AX, Wang X (2003) Transcription factors in liver development, differentiation, and regeneration. Hepatology 38:1331–1347

    PubMed  CAS  Google Scholar 

  • DeLaForest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA (2011) HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138:4143–4153

    Article  PubMed  CAS  Google Scholar 

  • Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001a) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403

    Article  PubMed  CAS  Google Scholar 

  • Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001b) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403

    Article  PubMed  CAS  Google Scholar 

  • Hemavathy K, Ashraf SI, Ip YT (2000) Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene 257:1–12

    Article  PubMed  CAS  Google Scholar 

  • Hernandez A, Marcos R (2008) Genetic variations associated with interindividual sensitivity in the response to arsenic exposure. Pharmacogenomics 9:1113–1132

    Article  PubMed  CAS  Google Scholar 

  • Hernandez A, Sampayo-Reyes A, Marcos R (2011) Identification of differentially expressed genes in the livers of chronically i-as-treated hamsters. Mutat Res 713:48–55

    Article  PubMed  CAS  Google Scholar 

  • Huang CF, Chen YW, Yang CY, Tsai KS, Yang RS, Liu SH (2011) Arsenic and diabetes: current perspectives. Kaohsiung J Med Sci 27:402–410

    Article  PubMed  CAS  Google Scholar 

  • IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004) Some drinking-water disinfectants and contaminants, including arsenic. IARC Monogr Eval Carcinog Risks Hum 84:1–477

    Google Scholar 

  • Ishiyama T, Kano J, Minami Y, Iijima T, Morishita Y, Noguchi M (2003) Expression of HNFs and C/EBP alpha is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes. Cancer Sci 94:757–763

    Article  PubMed  CAS  Google Scholar 

  • Jeannot E, Poussin K, Chiche L, Bacq Y, Sturm N, Scoazec JY, Buffet C, Van Nhieu JT, Bellanne-Chantelot C, de Toma C, Laurent-Puig P, Bioulac-Sage P, Zucman-Rossi J (2007) Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma. Cancer Res 67:2611–2616

    Article  PubMed  CAS  Google Scholar 

  • Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A (2007) Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 282:22089–22101

    Article  PubMed  CAS  Google Scholar 

  • Kalkuhl A, Kaestner K, Buchmann A, Schwarz M (1996) Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours. Carcinogenesis 17:609–612

    Article  PubMed  CAS  Google Scholar 

  • Kurrey NK, Amit, K, Bapat SA (2005) Snail and slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol 97:155–165

    Google Scholar 

  • Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068

    Article  PubMed  CAS  Google Scholar 

  • Lazarevich NL, Cheremnova OA, Varga EV, Ovchinnikov DA, Kudrjavtseva EI, Morozova OV, Fleishman DI, Engelhardt NV, Duncan SA (2004) Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 39:1038–1047

    Article  PubMed  CAS  Google Scholar 

  • Lazarevich NL, Fleishman DI (2008) Tissue-specific transcription factors in progression of epithelial tumors. Biochemistry (Mosc) 73:573–591

    Article  CAS  Google Scholar 

  • Liu J, Waalkes MP (2008) Liver is a target of arsenic carcinogenesis. Toxicol Sci 105:24–32

    Article  PubMed  CAS  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  PubMed  CAS  Google Scholar 

  • Morelli C, Campioni K, Parolin C, Palu G, Tognon M (2004) Activity of the matrix metalloproteinase-9 promoter in human normal and tumor cells. J Cell Physiol 199:126–133

    Article  PubMed  CAS  Google Scholar 

  • Navas-Acien A, Silbergeld EK, Streeter RA, Clark JM, Burke TA, Guallar E (2006) Arsenic exposure and type 2 diabetes: a systematic review of the experimental and epidemiological evidence. Environ Health Perspect 114:641–648

    Article  PubMed  CAS  Google Scholar 

  • Ning BF, Ding J, Yin C, Zhong W, Wu K, Zeng X, Yang W, Chen YX, Zhang JP, Zhang X, Wang HY, Xie WF (2010) Hepatocyte nuclear factor 4alpha suppresses the development of hepatocellular carcinoma. Cancer Res 70:7640–7651

    Article  PubMed  CAS  Google Scholar 

  • Ninomiya T, Hayashi Y, Saijoh K, Ohta K, Yoon S, Nakabayashi H, Tamaoki T, Kasuga M, Itoh H (1996) Expression ratio of hepatocyte nuclear factor-1 to variant hepatocyte nuclear factor-1 in differentiation of hepatocellular carcinoma and hepatoblastoma. J Hepatol 25:445–453

    Article  PubMed  CAS  Google Scholar 

  • Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    Article  PubMed  CAS  Google Scholar 

  • Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA (2003) Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34:292–296

    Article  PubMed  CAS  Google Scholar 

  • Pontoglio M, Sreenan S, Roe M, Pugh W, Ostrega D, Doyen A, Pick AJ, Baldwin A, Velho G, Froguel P, Levisetti M, Bonner-Weir S, Bell GI, Yaniv M, Polonsky KS (1998) Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J Clin Invest 101:2215–2222

    Article  PubMed  CAS  Google Scholar 

  • Shepherd M, Ellis I, Ahmad AM, Todd PJ, Bowen-Jones D, Mannion G, Ellard S, Sparkes AC, Hattersley AT (2001) Predictive genetic testing in maturity-onset diabetes of the young (MODY). Diabet Med 18:417–421

    Article  PubMed  CAS  Google Scholar 

  • Sicklick JK, Choi SS, Bustamante M, McCall SJ, Perez EH, Huang J, Li YX, Rojkind M, Diehl AM (2006) Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 291:G575–G583

    Article  PubMed  CAS  Google Scholar 

  • Singh AP, Goel RK, Kaur T (2011) Mechanisms pertaining to arsenic toxicity. Toxicol Int 18:87–93

    Article  PubMed  Google Scholar 

  • Straif K, Benbrahim-Tallaa L, Baan R, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Guha N, Freeman C, Galichet L, Cogliano V, WHO International Agency for Research on Cancer Monograph Working Group (2009) A review of human carcinogens—part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10:453–454

    Google Scholar 

  • Sun Y, Tokar EJ, Waalkes MP (2012) Overabundance of putative cancer stem cells in human skin keratinocyte cells malignantly transformed by arsenic. Toxicol Sci 125:20–29

    Google Scholar 

  • Tokar EJ, Diwan BA, Waalkes MP (2010) Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype. Environ Health Perspect 118:108–115

    PubMed  CAS  Google Scholar 

  • Tokar EJ, Qu W, Waalkes MP (2011) Arsenic, stem cells, and the developmental basis of adult cancer. Toxicol Sci 120(Suppl 1):S192–S203

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Germolec DR, Trempus CS, Cannon RE, Tokar EJ, Tennant RW, Ward JM, Diwan BA (2008) Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res 68:8278–8285

    Article  PubMed  CAS  Google Scholar 

  • Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, Look AT (2005) Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123:641–653

    Article  PubMed  CAS  Google Scholar 

  • Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (1996) Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460

    Article  PubMed  CAS  Google Scholar 

  • Yin C, Lin Y, Zhang X, Chen YX, Zeng X, Yue HY, Hou JL, Deng X, Zhang JP, Han ZG, Xie WF (2008) Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology 48:1528–1539

    Article  PubMed  CAS  Google Scholar 

  • Yu D, Wang ZH, Cheng SB, Li HK, Chan HB, Chew EC (2001) The effect of arsenic trioxide on the expression of hsc and HNF4 in nuclear matrix proteins in HepG2 cells. Anticancer Res 21:2553–2559

    PubMed  CAS  Google Scholar 

  • Zeng X, Lin Y, Yin C, Zhang X, Ning BF, Zhang Q, Zhang JP, Qiu L, Qin XR, Chen YX, Xie WF (2011) Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 54:2036–2047

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the “Generalitat de Catalunya” [2009SGR-725], the “Autonomous University of Barcelona” [APOSTA-2011 to A.H] and the “Spanish Ministry of Education and Science” [SAF2008-02933, SAF2011-23146 and FPI-MICINN-2009 to A.P].

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departament de Genètica i de Microbiologia, Facultat de Biociències, Grup de Mutagènesi, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Bellaterra, Spain

    Anna Pastoret, Ricard Marcos & Alba Hernandez

  2. CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain

    Ricard Marcos & Alba Hernandez

  3. Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS), Monterrey, Mexico

    Adriana Sampayo-Reyes, Odila Saucedo-Cardenas & Gerardo H. Lozano-Garza

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  1. Anna Pastoret
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Correspondence to Alba Hernandez.

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204_2012_948_MOESM2_ESM.tif

Supplementary material Short-term HepG2 exposure to sub-toxic doses of arsenite. Exposure of HepG2 cells to sub-toxic doses of arsenite for 48 h is able to reduce the expression of several members of the Hepatocyte Nuclear Factor (HNF) network at the mRNA (A) and the protein (B) level. Data are presented as mean values or representative experiments (n = 3–6); error bars correspond to 95 % confidence intervals. P values are two-sided (Student-t test). a P < 0.05 compared with time-matched controls. b P < 0.01 compared with time-matched controls. c P < 0.001 compared with time-matched controls. (TIFF 18805 kb)

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Pastoret, A., Marcos, R., Sampayo-Reyes, A. et al. Inhibition of hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) as a mechanism of arsenic carcinogenesis. Arch Toxicol 87, 1001–1012 (2013). https://doi.org/10.1007/s00204-012-0948-6

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  • DOI: https://doi.org/10.1007/s00204-012-0948-6

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