p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial-mesenchymal transition and cell proliferation

Tatsuki Yaginuma, Jing Gao, Kengo Nagata, Ryusuke Muroya, Huang Fei, Haruki Nagano, Sakura Chishaki, Takuma Matsubara, Shoichiro Kokabu, Kou Matsuo, Tamotsu Kiyoshima, Izumi Yoshioka, Eijiro Jimi

研究成果: Contribution to journalArticle査読

抄録

Bone invasion is a critical factor in determining the prognosis of oral squamous cell carcinoma (OSCC) patients. Transforming growth factor β (TGF-β) is abundantly expressed in the bone matrix and is involved in the acquisition of aggressiveness by tumors. TGF-β is also important to cytoskeletal changes during tumor progression. In this study, we examined the relationship between TGF-β signaling and cytoskeletal changes during bone invasion by OSCC. Immunohistochemical staining of OSCC samples from five patients showed the expression of p130Cas (Crk-associated substrate) in the cytoplasm and phosphorylated Smad3 expression in the nucleus in OSCC cells. TGF-β1 induced the phosphorylation of Smad3 and p130Cas, as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse squamous cell carcinome VII (SCCVII) cells. SB431542, a specific inhibitor of Smad2/3 signaling, abrogated the TGF-β1-induced phosphorylation of p130Cas and morphological changes. Silencing p130Cas using an short hairpin RNA (shRNA) or small interfering RNA in SCCVII cells suppressed TGF-β1-induced cell migration, invasion, EMT and matrix metalloproteinase-9 (MMP-9) production. Compared with control SCCVII cells, SCCVII cells with silenced p130Cas strongly suppressed zygomatic and mandibular destruction in vivo by reducing the number of osteoclasts, cell proliferation and MMP-9 production. Taken together, these results showed that the expression of TGF-β/p130Cas might be a new target for the treatment of OSCC bone invasion.

本文言語英語
ページ(範囲)1038-1048
ページ数11
ジャーナルCarcinogenesis
41
8
DOI
出版ステータス出版済み - 8 12 2020

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