Smad7 suppresses HCC development in a DEN induced mouse model

Introduction: Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. The transforming growth factor-β (TGF-β) signaling pathway plays a critical role in cancer progression. Smad7, a TGF-β target gene, acts as physiological feedback inhibitor of TGF-β and has been found tumorigenic in several tumors. Knowledge about the role of Smad7 in HCC is limited so far. This study investigated the potential effects of Smad7 in a DEN induced HCC mouse model.

Methods: Hepatocyte specific Smad7 transgenic mice were generated by crossing TTR-Cre mice with Alb-Smad7 transgenic mice. For the induction of HCC, two weeks old mice were injected intraperitoneally (i.p.) with 25 mg/kg DEN (Sigma). At 9 months of age, mice were sacrificed and livers were processed for further analysis. To induce Smad7 expression, 4 weeks old mice were injected with 1 mg/mice/day Tamoxifen (Sigma, T5648) for 5 days. Tamoxifen was dissolved in a pH neutral medium chain triglyceride (Neutralöl, Euro OTC Pharma) at a final concentration of 10 mg/ml.

Results: Expression of transgenic Smad7 was confirmed with RT-PCR and by immunohistochemistry. Compared to wild type, Smad7 transgenic mice showed a significantly lower tumor number.

Discussion/Conclusion: The results suggest that Smad7 plays an inhibitory role in the development of DEN induced HCC in mice. We currently use hepatocyte specific inducible Smad7 knock out animals to confirm our findings. Since Smad7 has both TGF-β dependent and independent functions, the detailed molecular mechanism how Smad7 affects the TGF-β or other pathways in this process needs to be further investigated.

Corresponding author: Meindl-Beinker, Nadja M

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