Research Papers:

TRKB tyrosine kinase receptor is a potential therapeutic target for poorly differentiated oral squamous cell carcinoma

Kazumasa Moriwaki, Yusuke Ayani, Hiroko Kuwabara, Tetsuya Terada, Ryo Kawata and Michio Asahi _

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Oncotarget. 2018; 9:25225-25243. https://doi.org/10.18632/oncotarget.25396

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Kazumasa Moriwaki1,*, Yusuke Ayani2,*, Hiroko Kuwabara3, Tetsuya Terada2, Ryo Kawata2 and Michio Asahi1

1Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan

2Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan

3Department of Pathology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan

*These authors contributed equally to this work

Correspondence to:

Michio Asahi, email: [email protected]

Keywords: TRKB; oral squamous cell carcinoma; tumor differentiation; prognostic factors; anti-cancer drug

Received: August 09, 2017     Accepted: April 26, 2018     Published: May 18, 2018


It has been reported that one of the neurotrophin receptors, tropomyosin receptor kinase B (TRKB), is frequently overexpressed in various tumor tissues including oral squamous cell carcinoma (OSCC), and that its upregulation promotes tumor progression in human cancers. However, the correlation between TRKB overexpression and clinicopathological characteristics is not fully elucidated. Here, we present the correlation between the expression levels of TRKB and/or its secreted ligand, brain-derived neurotrophic factor (BDNF), and clinicopathological characteristics, especially regarding tumor differentiation, tissue invasion, and disease-free survival in patients with OSCC. The results obtained through immunohistochemical analysis of human OSCC tumor specimens showed that the expression levels of TRKB and/or BDNF, were significantly higher in moderately and poorly differentiated OSCC (MD/PD-OSCC) tumor cells than in well differentiated cells (WD-OSCC). Moreover, the OSCC tumors highly expressing TRKB and/or BDNF exhibited promotion in tissue invasion and reduction in disease-free survival in the patients. In an orthotopic transplantation mouse model of human OSCC cell lines, administration of a TRKB-specific inhibitor significantly suppressed the tumor growth and invasion in PD-OSCC-derived tumor cells, but not in WD-OSCC-derived tumor cells. Moreover, the TRKB inhibitor selectively blocked BDNF-induced tumor cell proliferation and migration accompanied with the suppression of TRKB phosphorylation in PD-OSCC but not in WD-OSCC in vitro. Taken together, these data suggest that the BDNF/TRKB signaling pathway may regulate tumor progression in poorly differentiated OSCC. Expression levels of signal molecules may be an accurate prognosis marker for tumor aggressiveness, and the molecules may be an attractive target for new OSCC therapies.

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