title: Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice.
abstract: TGF-β 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-β 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.
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dzieran
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dropmann
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Maass
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Teufel
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Marhenke
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Rückert
authors.affiliation: Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kleiter
authors.affiliation: Department of Internal Medicine 2, Leopoldina-Hospital Schweinfurt, Schweinfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kanzler
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: M P
authors.initials: MP
authors.lastname: Ebert
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Vogel
authors.affiliation: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, RC Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: N M
authors.initials: NM
authors.lastname: Meindl-Beinker