Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice.

TGF-ß signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-ß signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and corresponding SMAD7 transgenic mice 9 months after diethylnitrosamine (DEN) challenge, verifying SMAD7 as a tumor suppressor in HCC. In line with our findings in patients, Smad7 levels in both tumor tissue as well as surrounding tissue show a significant inverse correlation with tumor numbers. SMAD7 KO mice presented with increased pSMAD2/3 levels and decreased apoptosis in the tumor tissue. Higher tumor incidence was accompanied by reduced P21 and upregulated c-MYC expression in the tumors. Activation of signal transducer and activator of transcription factor 3 signaling was found in Smad7-deficient mouse tumors and in patients with low tumoral SMAD7 expression as compared with surrounding tissue. Together, our results provide new mechanistic insights into the tumor-suppressive functions of SMAD7 in hepatocarcinogenesis.

Estradiol concentration and the regulation of locomotor activity.

We predicted that female prairie voles (Microtus ochrogaster) would not increase in locomotor activity during "induced" proestrus. We developed and tested two alternative a priori hypotheses to explain this predicted lack of activity. The Non-Response Hypothesis in which voles cannot, physiologically, increase activity in response to estradiol and, the Threshold Effect Hypothesis in which a minimal concentration of estradiol is necessary to achieve estrus, while higher concentrations influence other behavioral parameters. The non-response hypothesis predicts that hormone concentration will not affect locomotor activity, while the threshold effects hypothesis predicts that voles achieve estrus at low concentrations, while higher concentrations should trigger increasing locomotor activity. Initial results using running wheels indicated that females decreased activity during induced proestrus. Radioimmunoassay revealed that induced proestrus was achieved at relatively low concentrations of estradiol. Results from a dose response experiment allowed for rejection of the nonresponse hypothesis and supported the threshold effects hypothesis as females decreased activity at low concentrations of estradiol, showed no relative change at moderate concentrations, and increased activity at higher concentrations.