Open Access Research article

ITGA3 and ITGB4 expression biomarkers estimate the risks of locoregional and hematogenous dissemination of oral squamous cell carcinoma

Masaki Nagata1*, Arhab A Noman1, Kenji Suzuki2, Hiroshi Kurita3, Makoto Ohnishi4, Tokio Ohyama4, Nobutaka Kitamura5, Takanori Kobayashi1, Kohya Uematsu1, Katsu Takahashi6, Naoki Kodama1, Tomoyuki Kawase7, Hideyuki Hoshina1, Nobuyuki Ikeda1, Susumu Shingaki8 and Ritsuo Takagi1

Author Affiliations

1 Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori 2-5274, Chuo-ku, Niigata 951-8514, Japan

2 Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1-757, Chuo-ku, Niigata 951-8510, Japan

3 Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan

4 Division of Dental Clinic and Oral Surgery, Nagaoka Red Cross Hospital, Terashimamachi 297-1, Nagaoka 940-2085, Japan

5 Department of Medical Informatics, Niigata University Medical & Dental Hospital, Asahimachi-dori 1-754, Chuo-ku, Niigata 951-8520, Japan

6 Department of Oral and Maxillofacial Surgery, Kyoto University Graduate School of Medicine, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

7 Division of Oral Bioengineering, Department of Tissue Regeneration and Reconstitution, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori 2-5274, Chuo-kuNiigata 951-8514, Japan

8 Division of Reconstructive Surgery for Oral and Maxillofacial Region, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori 2-5274, Chuo-ku, Niigata 951-8514, Japan

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BMC Cancer 2013, 13:410  doi:10.1186/1471-2407-13-410

Published: 5 September 2013



Molecular biomarkers are essential for monitoring treatment effects, predicting prognosis, and improving survival rate in oral squamous cell carcinoma. This study sought to verify the effectiveness of two integrin gene expression ratios as biomarkers.


Gene expression analyses of integrin α3 (ITGA3), integrin β4 (ITGB4), CD9 antigen (CD9), and plakoglobin (JUP) by quantitative real-time PCR were conducted on total RNA from 270 OSCC cases. The logrank test, Cox proportional hazards model, and Kaplan-Meier estimates were performed on the gene expression ratios of ITGA3/CD9 and ITGB4/JUP and on the clinicopathological parameters for major clinical events.


A high rate (around 80%) of lymph node metastasis was found in cases with a high ITGA3/CD9 ratio (high-ITGA3/CD9) and invasive histopathology (YK4). Primary site recurrence (PSR) was associated with high-ITGA3/CD9, T3-4 (TNM class), and positive margin, indicating that PSR is synergistically influenced by treatment failure and biological malignancy. A high ITGB4/JUP ratio (high-ITGB4/JUP) was revealed to be a primary contributor to distant metastasis without the involvement of clinicopathological factors, suggesting intervention of a critical step dependent on the function of the integrin β4 subunit. Kaplan-Meier curves revealed positive margin as a lethal treatment consequence in high-ITGA3/CD9 and YK4 double-positive cases.


Two types of metastatic trait were found in OSCC: locoregional dissemination, which was reflected by high-ITGA3/CD9, and distant metastasis through hematogenous dissemination, uniquely distinguished by high-ITGB4/JUP. The clinical significance of the integrin biomarkers implies that biological mechanisms such as cancer cell motility and anchorage-independent survival are vital for OSCC recurrence and metastasis.

Squamous cell carcinoma; Biomarker; Metastasis; Integrin alpha3; Integrin beta4