␤-Catenin is a key mediator of the Wnt pathway, which plays a critical role in embryogenesis and oncogenesis. As a transcriptional activator, ␤-catenin binds the transcription factors, T-cell factor and lymphoid enhancer factor, and regulates gene expression in response to Wnt signaling. Abnormal activation of ␤-catenin has been linked to various types of cancer. In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel ␤-catenin-interacting protein. Here we show specific interaction of FHL2 with ␤-catenin, which requires the intact structure of FHL2 and armadillo repeats 1-9 of ␤-catenin. FHL2 cooperated with ␤-catenin to activate T-cell factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In contrast, coexpression of ␤-catenin and FHL2 had no synergistic effect on androgen receptor-mediated transcription, whereas each of these two coactivators independently stimulated AR transcriptional activity. Thus, the ability of FHL2 to stimulate the trans-activating function of ␤-catenin might be dependent on the promoter context. The detection of increased FHL2 expression in hepatoblastoma, a liver tumor harboring frequent ␤-catenin mutations, suggests that FHL2 might enforce ␤-catenin transactivation activity in cancer cells. These findings reveal a new function of the LIM coactivator FHL2 in transcriptional activation of Wnt-responsive genes.

H epatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of death by cancer worldwide. Epidemiologic studies have shown that more than 70% of HCC cases are linked to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Other risk factors include alcohol-related cirrhosis, dietary intake of aflatoxin B1 in some tropical areas, and inherited metabolic disorders such as tyrosinemia, hemochromatosis, and ␣1-antitrypsin deficiency. Recent insights into the mechanisms underlying HCC development have been provided by genome-wide allelotype studies and comparative genomic hybridization, showing numerous chromosomal changes during tumor development and progression. 1-5 These studies have led to the identification of a number of host factors as culprits in liver malignancy. Notably, allelic imbalance at chromosome 17p13 and frequent mutations of the p53 gene have been correlated with exposure to aflatoxin B1 and chronic HBV infection. 3 Mutations of ␤-catenin or its binding partner axin1, leading to abnormal activation of the Wnt pathway, have been implicated in about one third of HCC cases. 6,7 Among other common alterations, the long arm of chromosome 16 is a region of frequent loss of heterozygosity (LOH) in HCC, with deletion rates ranging from 28% to 70% in different studies. [8][9][10][11] This chromosomal arm carries a cluster of cadherin genes located at 16q22.1, and it has been proposed that deregulation of E-cadherin might be involved in liver carcinogenesis. [12][13][14][15]

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The chromosome 8p is associated with a large number of allelic imbalances in epithelial tumors including hepatocellular carcinoma (HCC). However, no tumor suppressor gene has been identi®ed so far in this particular region of the genome. To further clarify the pattern of allelic deletions on chromosome 8p in HCC, we have undertaken high-density polymorphic marker analysis of 109 paired normal and primary tumor samples using 40 microsatellites positioned every 2 cm in average throughout 8p. We found that 60% of the tumors exhibited loss of heterozygosity (LOH) at one or more loci at 8p with three distinct minimal deleted areas : a 13 cm region in the distal part of 8p21, a 9 cm area in the more proximal portion of 8p22 and a 5 cm area in 8p23. These data strongly suggest the presence of at least three novel tumor suppressor loci on 8p in hepatocellular carcinoma.

Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.

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We carried out a comparative analysis of several proposed host protein partners of the human hepatitis B virus X protein (HBx) using both the GAL4-and the LexA-based yeast two-hybrid system. We showed that the interaction of HBx with the UV-damaged DNA-binding protein (UVDDB) is positive in both yeast systems, detectable in cotransfected human cells, conserved by rodent hepadnavirus X proteins (known to transactivate in human cells), and tightly correlated with the transactivation proficiency of X-insertion mutants. Taken together, our results strongly suggest that UVDDB is involved in X-mediated transactivation.