Network Modeling of TGFβ Signaling in Hepatocellular Carcinoma Epithelial-to-Mesenchymal Transition Reveals Joint Sonic Hedgehog and Wnt Pathway Activation

被引:173
作者
Steinway, Steven Nathaniel [1 ]
Zanudo, Jorge G. T. [2 ]
Ding, Wei [3 ]
Rountree, Carl Bart [4 ]
Feith, David J. [5 ]
Loughran, Thomas P., Jr. [5 ]
Albert, Reka [2 ]
机构
[1] Penn State Coll Med, Penn State Hershey Canc Inst, Hershey, PA 17033 USA
[2] Penn State Univ, Dept Phys, University Pk, PA 16802 USA
[3] Penn State Coll Med, Dept Pediat, Hershey, PA 17033 USA
[4] Bon Secours St Marys Hosp, Dept Pediat Gastroenterol, Richmond, VA USA
[5] Univ Virginia, Sch Med, Ctr Canc, Charlottesville, VA 22908 USA
基金
美国国家科学基金会;
关键词
GROWTH-FACTOR-BETA; TRANSDUCTION NETWORKS; TUMOR PROGRESSION; SYSTEMS BIOLOGY; EXPRESSION; CANCER; CELLS; TRANSCRIPTION; MECHANISMS; RECEPTORS;
D O I
10.1158/0008-5472.CAN-14-0225
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is TGF beta, which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGF beta. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGF beta signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion, and metastasis in HCC. (C) 2014 AACR.
引用
收藏
页码:5963 / 5977
页数:15
相关论文
共 52 条
  • [1] Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma
    Abou-Shady, M
    Baer, HU
    Friess, H
    Berberat, P
    Zimmermann, A
    Graber, H
    Gold, LI
    Korc, M
    Büchler, MW
    [J]. AMERICAN JOURNAL OF SURGERY, 1999, 177 (03) : 209 - 215
  • [2] Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease
    Acloque, Herve
    Adams, Meghan S.
    Fishwick, Katherine
    Bronner-Fraser, Marianne
    Angela Nieto, M.
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (06) : 1438 - 1449
  • [3] Combinatorial drug therapy for cancer in the post-genomic era
    Al-Lazikani, Bissan
    Banerji, Udai
    Workman, Paul
    [J]. NATURE BIOTECHNOLOGY, 2012, 30 (07) : 679 - 691
  • [4] Boolean network simulations for life scientists
    Albert, Istvan
    Thakar, Juilee
    Li, Song
    Zhang, Ranran
    Albert, Reka
    [J]. SOURCE CODE FOR BIOLOGY AND MEDICINE, 2008, 3 (01):
  • [5] Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005
    Altekruse, Sean F.
    McGlynn, Katherine A.
    Reichman, Marsha E.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (09) : 1485 - 1491
  • [6] Amin Rupen, 2008, Gastrointest Cancer Res, V2, pS27
  • [7] Network medicine: a network-based approach to human disease
    Barabasi, Albert-Laszlo
    Gulbahce, Natali
    Loscalzo, Joseph
    [J]. NATURE REVIEWS GENETICS, 2011, 12 (01) : 56 - 68
  • [8] Mechanisms of nitric oxide-mediated inhibition of EMT in cancer Inhibition of the metastasis-inducer snail and induction of the metastasis-suppressor RKIP
    Baritaki, Stavroula
    Huerta-Yepez, Sara
    Sahakyan, Anna
    Karagiannides, Iordanis
    Bakirtzi, Kyriaki
    Jazirehi, Ali
    Bonavida, Benjamin
    [J]. CELL CYCLE, 2010, 9 (24) : 4931 - 4940
  • [9] Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours
    Dahmane, N
    Lee, J
    Robins, P
    Heller, P
    Altaba, ARI
    [J]. NATURE, 1997, 389 (6653) : 876 - 881
  • [10] Smad-dependent and Smad-independent pathways in TGF-β family signalling
    Derynck, R
    Zhang, YE
    [J]. NATURE, 2003, 425 (6958) : 577 - 584