3A) Albeit remarkable, these differences were not statistically

3A). Albeit remarkable, these differences were not statistically different.

Similarly, a slight up-regulation of tumor necrosis factor α mRNA (two-fold to six-fold) was detected in Mcl-1Δhep mice compared to WT and Mcl-1flox/wt mice (data not shown). In contrast, mRNA levels of interleukin 1β (IL1β and interferon gamma (IFNγ) were not different (Fig. 3A). Remarkably, livers of Mcl-1Δhep mice revealed scattered cells immunoreactive for the cytokine TGFβ, an important inducer of carcinogenesis, which were not detectable in control mice (Fig. 3B). Next, we addressed whether the relative increase of liver weight in Mcl-1Δhep animals and the strong up-regulation of Survivin might be linked to a higher hepatocyte proliferation rate, which we had observed previously in 4-month-old mice.10 Indeed, this website Mcl-1Δhep mice revealed a highly significant increase of Ki67+ hepatocytes compared to WT and heterozygous Mcl-1flox/wt mice at the age

of 8 and 12 months (P Selleck Veliparib < 0.0001, and P < 0.001, respectively; Fig. 3C). Remarkably, heterozygous Mcl-1flox/wt livers also displayed increased proliferation indices compared to WT livers. Quantification by BrdU incorporation corroborated this finding: Livers of 8-month-old Mcl-1Δhep mice still showed a significantly higher proliferation rate when compared to age-matched heterozygous Mcl-1flox/wt mice (P < 0.05; Fig. 3D). WT and heterozygous Mcl-1flox/wt mice revealed macroscopically normal livers at the age of 8 and 12 months. This was in contrast to age-matched Mcl-1Δhep livers which contained tumors in >50% of Mcl-1Δhep livers (Table 1). Liver tumors ranged from ∼2 mm to 3 cm in diameter (Fig. 4A). In addition, nontumorous parts of Mcl-1Δhep livers revealed a spectrum of findings ranging from a macroscopically unremarkable (some animals) to a strongly nodular (most animals) structure (Fig. 3A). Histologic analysis confirmed that ∼50% of all Mcl-1Δhep mice (11/21) see more displayed liver tumors (Fig. 4B). Larger tumors showed cellular atypia, altered liver-architecture

with broadening of liver cell cords (highlighted by collagen IV staining), and loss of reticulin fibers (shown by Gomori staining). In addition, the proliferation rate again increased compared to nontumorous areas, and a focal pattern of strong immunoreactivity for glutamine synthetase was observed (Fig. 4C). These findings support that the tumors histologically qualified as HCC. Mcl-1–deficient livers displayed different staining patterns for the oval cell marker A6. Mostly, tumors and nontumorous tissues were A6-negative (A6−). However, in several instances A6+ tumors, surrounded by A6− liver tissue, were detected. Besides, we could also detect one A6− tumor surrounded by A6+ liver tissue (Fig. 4D).

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