Inhibition of hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) as a mechanism of arsenic carcinogenesis.
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.
Departament de Genètica i de Microbiologia, Facultat de Biociències, Grup de Mutagènesi, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Bellaterra, Spain.
Anna
A
Pastoret
Ricard
R
Marcos
Adriana
A
Sampayo-Reyes
Odila
O
Saucedo-Cardenas
Gerardo H
GH
Lozano-Garza
Alba
A
Hernandez
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008647:Mesocricetus; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors
D018053:Arsenites; D002274:Carcinogens, Environmental; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C000715187:Lin28A protein, human; C489427:MYC protein, human; C497764:NOTCH2 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D051883:Receptor, Notch2; D017670:Sodium Compounds; C017947:sodium arsenite; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005634:Fructose-Bisphosphate Aldolase; D005947:Glucose