title: ITGA3 and ITGB4 expression biomarkers estimate the risks of locoregional and hematogenous dissemination of oral squamous cell carcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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. nagata@dent.niigata-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagata
authors.forename: Arhab A
authors.initials: AA
authors.lastname: Noman
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurita
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Tokio
authors.initials: T
authors.lastname: Ohyama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kitamura
authors.forename: Takanori
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kohya
authors.initials: K
authors.lastname: Uematsu
authors.forename: Katsu
authors.initials: K
authors.lastname: Takahashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kodama
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawase
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hoshina
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ikeda
authors.forename: Susumu
authors.initials: S
authors.lastname: Shingaki
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Takagi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D039422:Integrin alpha3 / Q000235:genetics* / Q000378:metabolism; D039663:Integrin beta4 / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D060245:Tetraspanin 29 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D055815:Young Adult; D051185:gamma Catenin
chemical_list: D014408:Biomarkers, Tumor; D051180:Desmoplakins; C059834:ITGB4 protein, human; D039422:Integrin alpha3; D039663:Integrin beta4; C495292:JUP protein, human; D060245:Tetraspanin 29; D051185:gamma Catenin