title: Mucin1 shifts Smad3 signaling from the tumor-suppressive pSmad3C/p21(WAF1) pathway to the oncogenic pSmad3L/c-Myc pathway by activating JNK in human hepatocellular carcinoma cells.
abstract: Mucin1 (MUC1) is a transmembrane glycoprotein that acts as an oncogene in human hepatic tumorigenesis. Hepatocellular carcinoma (HCC) cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor beta (TGF-β) together with stimulation of its oncogenic activity as in MUC1 expressing HCC cells; however, molecular mechanisms remain largely unknown. Type I TGF-β receptor (TβRI) and c-Jun NH2-terminal kinase (JNK) differentially phosphorylate Smad3 mediator to create 2 phosphorylated forms: COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Here, we report that MUC1 overexpression in HCC cell lines suppresses TβRI-mediated pSmad3C signaling which involves growth inhibition by up-regulating p21(WAF1). Instead, MUC1 directly activates JNK to stimulate oncogenic pSmad3L signaling, which fosters cell proliferation by up-regulating c-Myc. Conversely, MUC1 gene silencing in MUC1 expressing HCC cells results in preserved tumor-suppressive function via pSmad3C, while eliminating pSmad3L-mediated oncogenic activity both in vitro and in vivo. In addition, high correlation between MUC1 and pSmad3L/c-Myc but not pSmad3C/p21(WAF1) expression was observed in HCC tissues from patients. Collectively, these results indicate that MUC1 shifts Smad3 signaling from a tumor-suppressive pSmad3C/p21(WAF1) to an oncogenic pSmad3L/c-Myc pathway by directly activating JNK in HCC cells, suggesting that MUC1 is an important target for HCC therapy.
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Qiongshu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Guomu
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Tanxiu
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhai
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shao
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Ni
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Tai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D018396:Mucin-1 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489427:MYC protein, human; D018396:Mucin-1; D016271:Proto-Oncogene Proteins c-myc; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D048670:MAP Kinase Kinase 4