Notch1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc.
OBJECTIVE
As 50% of patients of head and neck squamous carcinoma (HNSCC) exhibit poor prognosis, the identification of new therapeutic targets is required. Recently, there have been several reports about the correlation between Notch1 and HNSCC, but the precise mechanism is still obscure. Therefore, in this study, we examined the involvement of Notch1 in HNSCC by using HNSCC cell lines and surgical specimens.


METHODS
To investigate the role of Notch1 in HNSCC, we examined the effect of Notch inhibitor DAPT on cell growth, invasion, and tumorigenicity using five HNSCC cell lines in vitro and in vivo. We further examined that the correlation with Notch expression and clinical prognostic factors was evaluated by using 101 HNSCC surgical specimens.


RESULTS
DAPT reduced the nuclear expression of Notch and c-Myc and repressed cell growth, EMT-dependent cell invasion in vitro, and tumorigenicity in vivo. An overexpression of Myc enhanced EMT with an increase of Snail and vimentin together with decreased levels of E-cadherin in HSC3 cells. Finally, we discovered that Notch expression was well correlated with MIB-1 index and lymph node metastases.


CONCLUSIONS
We discovered that Notch1 was strongly correlated with HNSCC growth, invasion, and metastases. Therefore, Notch1 might be a new therapeutic target and a predictive marker of proliferation and metastasis of HNSCC.
Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Naoya
N
Inamura
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan. Electronic address: ktaichi@syd.odn.ne.jp.
Taichi
T
Kimura
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Lei
L
Wang
Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Hiroko
H
Yanagi
Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Masumi
M
Tsuda
Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Mishie
M
Tanino
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Hiroshi
H
Nishihara
Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Satoshi
S
Fukuda
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan; Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Shinya
S
Tanaka
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D003959:Diamines / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013844:Thiazoles / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism; D055815:Young Adult
C000612000:24-diamino-5-phenylthiazole; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D003959:Diamines; C489427:MYC protein, human; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D013844:Thiazoles; D014746:Vimentin
Growth; Head and neck cancer; Invasion; Notch1; Squamous cell carcinoma