title: Enhancement of DEN-induced liver tumourigenesis in hepatocyte-specific Lass2-knockout mice coincident with upregulation of the TGF-β1-Smad4-PAI-1 axis.
abstract: Longevity assurance homolog 2 of yeast LAG1 (Lass2) gene is capable of suppressing the proliferation and metastasis of several types of tumours including liver cancer. In the present study, hepatocyte-specific Lass2-knockout (Lass2 KO) and wild-type (WT) mice were exposed to the carcinogen, diethylnitrosamine (DEN), to induced liver tumours. At week 23 following DEN injection, tumours were produced in 100% of the Lass2 KO mice and 21.4% of the WT mice. At week 40, 100% of the Lass2 KO mice and 78.6% of the WT mice developed tumours, with no distinct significant difference in tumour occurrences between the two genotypes; yet, tumours in the Lass2 KO mouse livers were more numerous and larger in size. Hepatocellular carcinoma (HCC) was confirmed by α-fetoprotein (AFP). PCNA and EdU assays indicated more active proliferation whereas TUNEL assay revealed decreased apoptosis in Lass2 KO livers, when compared with the WT control. The expression of plasminogen activator inhibitor type-1 (PAI-1), a tumour-promoting gene, in the liver tissues of the 2 genotypes was detected using qPCR and western blotting, showing that PAI-1 levels were significantly elevated in Lass2 KO livers at week 40 following DEN introduction. Moreover, the expression of PAI-1-related TGF-β1, Smad-4 and -7 was detected, displaying an elevation in TGF-β1 and Smad-4 (not including Smad-7) in the Lass2 KO livers. Our data demonstrates that i) Lass2 is a protective gene against DEN-induced liver tumourigenesis; and ii) upregulation of the TGF-β1-Smad4-PAI-1 axis may contribute to the vulnerability of Lass2-knockout mice to DEN.
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China.
authors: Lufang
authors: L
authors: Chen
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Xiaodong
authors: X
authors: Lu
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Tiantian
authors: T
authors: Zeng
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Yuanyuan
authors: Y
authors: Chen
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Qian
authors: Q
authors: Chen
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Weijiang
authors: W
authors: Wu
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Xun
authors: X
authors: Yan
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Honghua
authors: H
authors: Cai
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Zhijian
authors: Z
authors: Zhang
authors: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors: Qixiang
authors: Q
authors: Shao
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China.
authors: Wenxin
authors: W
authors: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D004052:Diethylnitrosamine / Q000494:pharmacology*; D022781:Hepatocytes / Q000473:pathology; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D058258:Serpin E2 / Q000096:biosynthesis; D051901:Smad4 Protein / Q000096:biosynthesis; D051049:Sphingosine N-Acyltransferase / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D053773:Transforming Growth Factor beta1; D004052:Diethylnitrosamine; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase