Hence, our observation of common chromosomal changes in early and late tumors suggests that progression from adenoma to HCC may be a frequent event in the DEN mouse model. This represents a difference to adenomas in humans, which only infrequently progress to HCC. However, dysplastic nodules, which represent early lesions in human hepatocarcinogenesis are associated with loss of the 1p36-p34 region.38 A frequently

deleted chromosomal region in a tumor may harbor one or several suppressor genes critically involved in tumor initiation and/or progression. We therefore used bioinformatic tools Stem Cell Compound Library solubility dmso to screen for suppressor genes in the distal 4q region and, based on current knowledge, Runx3 (runt related transcription factor 3; human ortholog RUNX3) and Nr0b2 (nuclear receptor subfamily 0, group B, member 2 Gene; human ortholog NR0B2), also known as SHP (small heterodimer partner), MI-503 are the best candidate tumor suppressor genes. RUNX3 belongs to the Runt family of transcriptional factors that can activate or repress target gene transcription.42 Several studies have demonstrated that in human HCC the

expression and copy number of RUNX3 are reduced27 and promoter hypermethylation of RUNX3 occurs frequently.25, 26 The suppression of Notch signaling might be one of the molecular mechanisms for the negative effect of RUNX3 on the biology of HCC.28 Furthermore, RUNX3 may act as a coactivator for p53.43 NR0B2/SHP is a member of the nuclear receptor superfamily and participates in the biological regulation of several major functions of the liver. The expression of NR0B2/SHP is diminished in HCC and corresponding cell lines by epigenetic silencing owing to promoter hypermethylation.29 In fact, Shp−/− mice develop spontaneous HCC associated with enhanced hepatocyte proliferation and increased cyclin D1 expression.30, 31 Moreover, mice lacking SHPs upstream learn more regulator farnesoid X receptor (FXR), which is essential in regulating bile acid, lipid, and glucose homeostasis,44 also have an increased

susceptibility to hepatic carcinogenesis.45, 46 Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human HCC. Activation of β-catenin, the central effector of the canonical Wnt pathway, has also been implicated in the DEN-induced HCC mouse model.16, 32, 33 At present, the significance of β-catenin-activating mutations is discussed especially in the context of chromosomal instability and increase of susceptibility to DEN-induced HCC formation. Chromosome-unstable HCCs were reported to be associated with AXIN1 mutations, whereas chromosome-stable HCCs rather contain β-catenin mutations.35, 36 Other studies have provided evidence that β-catenin-activating mutations are involved in HCC initiation. For example, in a transgenic mouse overexpression of mutated β-catenin specifically in hepatocytes made these mice susceptible to DEN-induced HCC.