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PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis

Sohee Jun, Sunhye Lee, Han-Cheon Kim

    Cell Reports
    |November 12, 2013
    PubMed

    Insights

    PCNA-associated factor (PAF) drives pancreatic cancer by activating MAPK signaling independently of Ras mutations. PAF overexpression leads to LAMTOR3 activation, promoting cell proliferation and tumor development.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cell Signaling

    Background:

    • Mitogen-activated protein kinase (MAPK) signaling pathway dysregulation is a key driver in pancreatic cancer development.
    • While Ras-mutation-driven pancreatic cancer is understood, the mechanisms behind Ras-independent MAPK hyperactivation are unclear.

    Purpose of the Study:

    • To investigate the role of PCNA-associated factor (PAF) in pancreatic cancer pathogenesis.
    • To elucidate the mechanism by which PAF contributes to Ras-independent MAPK hyperactivation and pancreatic tumorigenesis.

    Main Methods:

    • Analysis of PAF expression in pancreatic cancer tissues and cell lines.
    • Utilized mouse models to study the effects of PAF expression on pancreatic intraepithelial neoplasia and cancer stem cell markers.
    • Investigated the impact of PAF on extracellular signal-regulated kinase (ERK) phosphorylation and its dependence on Ras/Raf mutations.
    • Examined the transcriptional regulation of LAMTOR3 by PAF and its role in MAPK/mTOR signaling.

    Main Results:

    • PAF is overexpressed in pancreatic cancer and essential for cancer cell proliferation.
    • PAF expression in mouse models induced pancreatic intraepithelial neoplasia and cancer stem cell markers.
    • PAF-induced ductal epithelial cell hyperproliferation and ERK phosphorylation occurred independently of Ras or Raf mutations.
    • PAF transcriptionally activates LAMTOR3, leading to MEK and ERK hyperphosphorylation, crucial for pancreatic cancer cell proliferation.

    Conclusions:

    • PAF plays a significant role in pancreatic tumorigenesis through a novel mechanism involving LAMTOR3.
    • PAF-induced MAPK hyperactivation, mediated by LAMTOR3, represents a potential therapeutic target for pancreatic cancer.

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