Role of TGF-beta and Smad7 in HCC development and progression

Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide. TGF-β is a driver of chronic liver disease progression, which eventually ends in HCC. TGF-β, a tumor suppressor in cancer development, exerts tumor promoting characteristics during cancer progression. This, together with a strong heterogeneity of HCC leads to a very complex situation in regard of TGF-β signaling in liver cancer.

Here we show that Smad7, an inhibitor of canonical TGF-β signaling, is overexpressed in 69% of 54 analyzed matched human HCC/normal liver samples indicating that TGF-β/Smad7 might be involved in hepatocarcinogenesis (Real Time PCR). To identify possible roles of these factors in HCC we investigated 9 different HCC cell lines: With one exception, Smad7 expression levels can be correlated to the TGF-β dependent activation of the canonical pathway (Western blot against p-Smad2, Smad3 reporter assay). Interestingly, functional assays revealed that there are no further correlations between the Smad7 expression and strength of the TGF-β response with TGF-β induced cell death, growth arrest or tumorigenicity. These findings probably reflect the different functions of TGF-β/Smad7 in HCC development and progression. Besides heterogeneity of the TGF-β response we show strongly varying autocrine TGF-β signaling in the cell lines. Further, cells with elevated Smad7 mRNA expression levels show increased TGF-β expression levels. These findings suggest a mechanism to protect cells from tumor suppressing TGF-β effects while parallely secreting TGF-β to surrounding non tumorigenic cells.

In summary, we suggest that Smad7 could represent a new marker for HCC. However, as it is known that TGF-β/Smad7 show ambiguous functions in carcinogenesis it is still unclear if or in which stage of tumorigenesis increased Smad7 levels fulfill tumor promoting or suppressing tasks. To understand the different mechanisms cell lines with various TGF-β outcomes can be used.