Selective inhibition of NF-κB suppresses bone invasion by oral squamous cell carcinoma in vivo

Authors

  • Hiroyuki Furuta,

    1. Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
    2. Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Kenji Osawa,

    1. Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Masashi Shin,

    1. Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
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  • Ayataka Ishikawa,

    1. Division of Oral Pathology, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Kou Matsuo,

    1. Division of Oral Pathology, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Masud Khan,

    1. Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
    2. Global Center of Excellence (G-COE) Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo Japan
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  • Kazuhiro Aoki,

    1. Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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  • Keiichi Ohya,

    1. Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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  • Masato Okamoto,

    1. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo Japan
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  • Kazuhiro Tominaga,

    1. Division of Maxillofacial Diagnostic and Surgical Science, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
    2. Center for Oral Biological Research, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Tetsu Takahashi,

    1. Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Osamu Nakanishi,

    1. Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
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  • Eijiro Jimi

    Corresponding author
    1. Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
    2. Center for Oral Biological Research, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
    • Division of Molecular Signaling and Biochemistry, Department of Biosciences, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan
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    • Tel.: +[81-93-285-3047], Fax: +[81-93-582-6000]


  • Conflicts of interest: The authors declare no conflict of interest.

Abstract

Nuclear factor-κB (NF-κB) is constitutively activated in many cancers, including oral squamous cell carcinoma (OSCC), and is involved in the invasive characteristics of OSCC, such as growth, antiapoptotic activity and protease production. However, the cellular mechanism underlying NF-κB's promotion of bone invasion by OSCC is unclear. Therefore, we investigated the role of NF-κB in bone invasion by OSCC in vivo. Immunohistochemical staining of OSCC invading bone in 10 patients indicated that the expression and nuclear translocation of p65, a main subunit of NF-κB, was increased in OSCC compared with normal squamous epithelial cells. An active form of p65 phosphorylated at serine 536 was present mainly in the nucleus in not only differentiated tumor cells but also tumor-associated stromal cells and bone-resorbing osteoclasts. We next injected mouse OSCC SCCVII cells into the masseter region of C3H/HeN mice. Mice were treated for 3 weeks with a selective NF-κB inhibitor, NBD peptide, which disrupts the association of NF-κB essential modulator (NEMO) with IκB kinases. NBD peptide treatment inhibited TNFα-induced and constitutive NF-κB activation in SCCVII cells in vitro and in vivo, respectively. Treatment with NBD peptide decreased zygoma and mandible destruction by SCCVII cells, reduced number of osteoclasts by inhibiting RANKL expression in osteoblastic cells and SCCVII cells, increased apoptosis and suppressed the proliferation of SCCVII cells. Taken together, our data clearly indicate that inhibition of NF-κB is useful for inhibiting bone invasion by OSCC.

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