Hepatocyte nuclear factors (HNF) play a critical role in development of the liver. Their roles during liver tumorigenesis and progression of hepatocellular carcinomas (HCC) are, however, poorly understood. To address the role of HNFs in tumor progression, we generated a new experimental model in which a highly differentiated slow-growing transplantable mouse HCC (sgHCC) rapidly gives rise in vivo to a highly invasive fast-growing dedifferentiated variant (fgHCC). This in vivo model has allowed us to investigate the fundamental mechanisms underlying HCC progression. A complete loss of cell polarity, a decrease in cell-cell and cell-extracellular matrix (ECM) adhesion, elevation of telomerase activity, and extinction of liver-specific gene expression accompanies tumor progression. Moreover, cells isolated from fgHCCs acquired the ability to proliferate rapidly in culture. These alterations were coupled with a reduced expression of several liver transcription factors including HNF4, a factor essential for hepatocyte differentiation. Forced re-expression of HNF4␣1 in cultured fgHCC cells reversed the progressive phenotype and induced fgHCC cells to reestablish an epithelium and reform cell-ECM contacts. Moreover, fgHCC cells that expressed HNF4␣1 also re-established expression of the profile of liver transcription factors and hepatic genes that are associated with a differentiated hepatocyte phenotype. Importantly, re-expression of HNF4␣1 in fgHCC reduced the proliferation rate in vitro and diminished tumor formation in congenic recipient mice. In conclusion, loss of HNF4 expression is an important determinant of HCC progression. Forced expression of this factor can promote reversion of tumors toward a less invasive highly differentiated slow-growing phenotype. (HEPATOLOGY 2004;39:1038 -1047 H epatocellular carcinoma (HCC) is one of the world's most common cancers, with chronic hepatitis B and C infection and prolonged exposure to hepatocarcinogens being the major risk factors. 1 The development of a malignant phenotype is considered a multi-step process that results from the accumulation of genetic alterations. The consequence of these alterations is the evolution of a tumor towards a more aggressive phenotype. HCC progression from a well differentiated to a less differentiated form is accompanied by striking changes in the morphological and genetic properties of the cells and is one of the most critical steps of liver tumorigenesis. 2,3 Hepatic tumor progression is defined by a decrease in differentiation, an extinction of tissue-specific gene expression, acceleration of cell proliferation, loss of epithelial morphology, increased invasiveness, and ultimately metastasis. While a variety of inter-and intracellular signaling pathways essential for the control of liver function and proliferation have been described, the mo-

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