An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis

被引：451

作者：

Hatziapostolou, Maria ^{[1
,2
]}

Polytarchou, Christos ^{[1
,2
]}

Aggelidou, Eleni ^{[4
]}

Drakaki, Alexandra ^{[5
]}

Poultsides, George A. ^{[6
]}

Jaeger, Savina A. ^{[7
]}

Ogata, Hisanobu ^{[8
]}

Karin, Michael ^{[8
]}

Struhl, Kevin ^{[3
]}

Hadzopoulou-Cladaras, Margarita ^{[4
]}

Iliopoulos, Dimitrios ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Aristotle Univ Thessaloniki, Dept Genet Dev & Mol Biol, Dev Biol Lab, Sch Biol, Thessaloniki 54124, Greece

[5] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med, Boston, MA 02215 USA

[6] Stanford Univ, Med Ctr, Dept Surg, Stanford, CA 94305 USA

[7] Novartis Inst Biomed Res, Dept Dev Mol Pathways, Cambridge, MA 02139 USA

[8] Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Sch Med, La Jolla, CA 92093 USA

来源：

CELL | 2011年 / 147卷 / 06期

基金：

美国国家卫生研究院;

关键词：

HEPATOCYTE NUCLEAR FACTOR-4-ALPHA; INTESTINAL EPITHELIAL-CELLS; OXIDATIVE STRESS; TRANSCRIPTION FACTORS; STAT3; ACTIVATION; ELEGANS GENOME; CANCER; CARCINOMA; EXPRESSION; MICRORNA;

D O I：

10.1016/j.cell.2011.10.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4 alpha initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4 alpha and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4 alpha circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

引用

页码：1233 / 1247

页数：15

共 44 条

[1] Hepatocyte nuclear factor 4α in the intestinal epithelial cells protects against inflammatory bowel disease [J].

Ahn, Sung-Hoon ;

Shah, Yatrik M. ;

Inoue, Junko ;

Morimura, Keiichirou ;

Kim, Insook ;

Yim, SunHee ;

Lambert, Gilles ;

Kurotani, Reiko ;

Nagashima, Kunio ;

Gonzalez, Frank J. ;

Inoue, Yusuke .

INFLAMMATORY BOWEL DISEASES, 2008, 14 (07) :908-920

[2] Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region [J].

Barrett, Jeffrey C. ;

Lee, James C. ;

Lees, Charles W. ;

Prescott, Natalie J. ;

Anderson, Carl A. ;

Phillips, Anne ;

Wesley, Emma ;

Parnell, Kirstie ;

Zhang, Hu ;

Drummond, Hazel ;

Nimmo, Elaine R. ;

Massey, Dunecan ;

Blaszczyk, Kasia ;

Elliott, Timothy ;

Cotterill, Lynn ;

Dallal, Helen ;

Lobo, Alan J. ;

Mowat, Craig ;

Sanderson, Jeremy D. ;

Jewell, Derek P. ;

Newman, William G. ;

Edwards, Cathryn ;

Ahmad, Tariq ;

Mansfield, John C. ;

Satsangi, Jack ;

Parkes, Miles ;

Mathew, Christopher G. ;

Donnelly, Peter ;

Peltonen, Leena ;

Blackwell, Jenefer M. ;

Bramon, Elvira ;

Brown, Matthew A. ;

Casas, Juan P. ;

Corvin, Aiden ;

Craddock, Nicholas ;

Deloukas, Panos ;

Duncanson, Audrey ;

Jankowski, Janusz ;

Markus, Hugh S. ;

McCarthy, Mark I. ;

Palmer, Colin N. A. ;

Plomin, Robert ;

Rautanen, Anna ;

Sawcer, Stephen J. ;

Samani, Nilesh ;

Trembath, Richard C. ;

Viswanathan, Ananth C. ;

Wood, Nicholas ;

Spencer, Chris C. A. ;

Bellenguez, Celine .

NATURE GENETICS, 2009, 41 (12) :1330-U99

[3] Stat3 as an oncogene [J].

Bromberg, JF ;

Wrzeszczynska, MH ;

Devgan, G ;

Zhao, YX ;

Pestell, RG ;

Albanese, C ;

Darnell, JE .

CELL, 1999, 98 (03) :295-303

[4] Ubiquitous activation of Ras and Jak/Stat pathways in human HCC [J].

Calvisi, DF ;

Ladu, S ;

Gorden, A ;

Farina, M ;

Conner, EA ;

Lee, JS ;

Factor, VM ;

Thorgeirsson, SS .

GASTROENTEROLOGY, 2006, 130 (04) :1117-1128

[5] Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium [J].

Cattin, Anne-Laure ;

Le Beyec, Johanne ;

Barreau, Frederick ;

Saint-Just, Susan ;

Houllier, Anne ;

Gonzalez, Frank J. ;

Robine, Sylvie ;

Pincon-Raymond, Martine ;

Cardot, Philippe ;

Lacasa, Michel ;

Ribeiro, Agnes .

MOLECULAR AND CELLULAR BIOLOGY, 2009, 29 (23) :6294-6308

[6] DISRUPTION OF THE HNF-4 GENE, EXPRESSED IN VISCERAL ENDODERM, LEADS TO CELL-DEATH IN EMBRYONIC ECTODERM AND IMPAIRED GASTRULATION OF MOUSE EMBRYOS [J].

CHEN, WS ;

MANOVA, K ;

WEINSTEIN, DC ;

DUNCAN, SA ;

PLUMP, AS ;

PREZIOSO, VR ;

BACHVAROVA, RF ;

DARNELL, JE .

GENES & DEVELOPMENT, 1994, 8 (20) :2466-2477

[7] Convergence of Wnt Signaling on the HNF4α-Driven Transcription in Controlling Liver Zonation [J].

Colletti, Marta ;

Cicchini, Carla ;

Conigliaro, Alice ;

Santangelo, Laura ;

Alonzi, Tonino ;

Pasquini, Emiliano ;

Tripodi, Marco ;

Amicone, Laura .

GASTROENTEROLOGY, 2009, 137 (02) :660-672

[8] Inflammation and cancer [J].

Coussens, LM ;

Werb, Z .

NATURE, 2002, 420 (6917) :860-867

[9] Hepatocyte Nuclear Factor-4α Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species [J].

Darsigny, Mathieu ;

Babeu, Jean-Philippe ;

Seidman, Ernest G. ;

Gendron, Fernand-Pierre ;

Levy, Emile ;

Carrier, Julie ;

Perreault, Nathalie ;

Boudreau, Francois .

CANCER RESEARCH, 2010, 70 (22) :9423-9433

[10] Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis [J].

El-Serag, Hashem B. ;

Rudolph, Lenhard .

GASTROENTEROLOGY, 2007, 132 (07) :2557-2576

← 1 2 3 4 5 →