The pathological significance of Notch1 in oral squamous cell carcinoma.
Notch signaling has been reported to be involved in several types of malignant tumors; however, the role and activation mechanism of Notch signaling in oral squamous cell carcinoma (OSCC) remains poorly characterized. The purpose of this study was to elucidate the pathological significance of Notch signaling and its activation mechanism in the development and progression of OSCC. In this study, we showed that the expression of Notch1 and intracellular Notch domain (NICD) are upregulated in OSCCs. In addition, Notch1 and NICD were found to be characteristically localized at the invasive tumor front. TNF-α, a major inflammatory cytokine, significantly activated Notch signaling in vitro. In a clinicopathological analysis, Notch1 expression correlated with both the T-stage and the clinical stage. Furthermore, loss of Notch1 expression correlated with the inhibition of cell proliferation and TNF-α-dependent invasiveness in an OSCC cell line. In addition, γ-secretase inhibitor (GSI) prevented cell proliferation and TNF-α-dependent invasion of OSCC cells in vitro. These results indicate that altered expression of Notch1 is associated with increased cancer progression and that Notch1 regulates the steps involved in cell metastasis in OSCC. Moreover, inactivating Notch signaling with GSI could therefore be a useful approach for treating patients with OSCC.
1] Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan [2] Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Ryoji
R
Yoshida
Masashi
M
Nagata
Hideki
H
Nakayama
Kanako
K
Niimori-Kita
Wael
W
Hassan
Takuji
T
Tanaka
Masanori
M
Shinohara
Takaaki
T
Ito
D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009367:Neoplasm Staging; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D051881:Receptor, Notch1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; C497763:Notch1 protein, rat; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases