HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

被引:73
作者
De Minicis, Samuele [1 ]
Agostinelli, Laura [1 ]
Rychlicki, Chiara [1 ]
Sorice, Gian Pio [2 ,3 ]
Saccomanno, Stefania [1 ]
Candelaresi, Cinzia [1 ]
Giaccari, Andrea [2 ,4 ]
Trozzi, Luciano [1 ]
Pierantonelli, Irene [1 ]
Mingarelli, Eleonora [1 ]
Marzioni, Marco [1 ]
Muscogiuri, Giovanna [2 ]
Gaggini, Melania [5 ]
Benedetti, Antonio [1 ]
Gastaldelli, Amalia [5 ]
Guido, Maria [6 ]
Svegliati-Baroni, Gianluca [1 ,7 ]
机构
[1] Univ Politecn Marche, Dept Gastroenterol, Ancona, Italy
[2] Univ Cattolica Sacro Cuore, Policlin Gemelli, Div Endocrinol & Metab Dis, Rome, Italy
[3] ACISMOM, Diabet Care Clin, Rome, Italy
[4] Don Gnocchi Fdn Onlus, Milan, Italy
[5] CNR, Inst Clin Physiol, Cardiometabol Risk Unit, I-56100 Pisa, Italy
[6] Univ Padua, Dept Med, Anat Pathol Unit, Padua, Italy
[7] Univ Politecn Marche, Obes Ctr, Ancona, Italy
关键词
NONALCOHOLIC FATTY LIVER; HEPATOCELLULAR-CARCINOMA; METABOLIC SYNDROME; HEPATIC STEATOSIS; IN-VIVO; DISEASE; CANCER; MECHANISMS; NAFLD; INFLAMMATION;
D O I
10.1371/journal.pone.0097136
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.
引用
收藏
页数:11
相关论文
共 50 条
[1]   OPINION Is NF-κB a good target for cancer therapy? Hopes and pitfalls [J].
Baud, Veronique ;
Karin, Michael .
NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (01) :33-40
[2]   Inflammation and Liver Cancer New Molecular Links [J].
Berasain, C. ;
Castillo, J. ;
Perugorria, M. J. ;
Latasa, M. U. ;
Prieto, J. ;
Avila, M. A. .
STEROID ENZYMES AND CANCER, 2009, 1155 :206-221
[3]   Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets [J].
Boyault, Sandrine ;
Rickman, David S. ;
de Reynies, Aurelien ;
Balabaud, Charles ;
Rebouissou, Sandra ;
Jeannot, Emmanuelle ;
Herault, Aurelie ;
Saric, Jean ;
Belghiti, Jacques ;
Franco, Dominique ;
Bioulac-Sage, Paulette ;
Laurent-Puig, Pierre ;
Zucman-Rossi, Jessica .
HEPATOLOGY, 2007, 45 (01) :42-52
[4]   Molecular mediators of hepatic steatosis and liver injury [J].
Browning, JD ;
Horton, JD .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (02) :147-152
[5]   Management of Hepatocellular Carcinoma: An Update [J].
Bruix, Jordi ;
Sherman, Morris .
HEPATOLOGY, 2011, 53 (03) :1020-1022
[6]   Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms [J].
Bugianesi, E ;
Gastaldelli, A ;
Vanni, E ;
Gambino, R ;
Cassader, M ;
Baldi, S ;
Ponti, V ;
Pagano, G ;
Ferrannini, E ;
Rizzetto, M .
DIABETOLOGIA, 2005, 48 (04) :634-642
[7]   Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications [J].
Burgess, Angela ;
Vanella, Luca ;
Bellner, Lars ;
Schwartzman, Michal L. ;
Abraham, Nader G. .
PROSTAGLANDINS & OTHER LIPID MEDIATORS, 2012, 97 (1-2) :1-16
[8]   Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma [J].
Calvisi, Diego F. ;
Wang, Chunmei ;
Ho, Coral ;
Ladu, Sara ;
Lee, Susie A. ;
Mattu, Sandra ;
Destefanis, Giulia ;
Delogu, Salvatore ;
Zimmermann, Antje ;
Ericsson, Johan ;
Brozzetti, Stefania ;
Staniscia, Tommaso ;
Chen, Xin ;
Dombrowski, Frank ;
Evert, Matthias .
GASTROENTEROLOGY, 2011, 140 (03) :1071-U542
[9]   IGF2: Epigenetic regulation and role in development and disease [J].
Chao, Wendy ;
D'Amore, Patricia A. .
CYTOKINE & GROWTH FACTOR REVIEWS, 2008, 19 (02) :111-120
[10]  
Day C P, 2005, Gastroenterology, V129, P375, DOI 10.1053/j.gastro.2005.05.041