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

Masaki Nagata,Tomoyuki Kawase,Takanori Kobayashi,Nobuyuki Ikeda,Nobutaka Kitamura,Arhab A Noman,Hideyuki Hoshina,Tokio Ohyama,Kohya Uematsu,Hiroshi Kurita,Susumu Shingaki,Katsu Takahashi,Ritsuo Takagi,Makoto Ohnishi,Naoki Kodama,Kenji Suzuki

doi:10.1186/1471-2407-13-410

Masaki Nagata, Tomoyuki Kawase + Show 14 more

Open Access

https://doi.org/10.1186/1471-2407-13-410

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Abstract

BackgroundMolecular 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.MethodsGene 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.ResultsA 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.ConclusionTwo 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.

Highlights

Molecular biomarkers are essential for monitoring treatment effects, predicting prognosis, and improving survival rate in oral squamous cell carcinoma
We report here that certain ITGA3/CD9 and ITGB4/JUP gene expression ratios are related to individual clinical events such as lymph node metastasis, primary site recurrence, distant metastasis, and uncontrollable death from Oral squamous cell carcinoma (OSCC)
Primary site recurrence (PSR) was significantly associated with high-ITGA3/CD9, tumor size, T3-4 and positive margin, while distant metastasis was associated with high-ITGA3/CD9, a high ITGB4/JUP ratio, and YK4

Summary

Introduction

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. Despite recent improvements survival rate and patient QOL, it is essential to fully understand the risks of locoregional recurrence and distant metastasis. We used microarray analysis and reverse transcription quantitative real time polymerase chain reaction (RT-QPCR) to report the potential use of integrin and tetraspanin family molecules as biomarkers for OSCC malignancy [14,15,16]. We report here that certain ITGA3/CD9 and ITGB4/JUP gene expression ratios are related to individual clinical events such as lymph node metastasis, primary site recurrence, distant metastasis, and uncontrollable death from OSCC

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