Use of NRP1, a novel biomarker, along with VEGF-C, VEGFR-3, CCR7 and SEMA3E, to predict lymph node metastasis in squamous cell carcinoma of the tongue.
Lymph node (LN) metastasis has been suggested as a major prognostic factor for oral cancer. Knockdown of the growth factors and receptors involved in these metastatic mechanisms could significantly reduce LN metastasis and improve the survival of oral cancer patients after treatment. The present study, therefore, aimed to evaluate the expression levels of the following growth factors and receptors in squamous cell carcinoma (SCC) of the tongue: the vascular endothelial growth factor (VEGF)‑C and VEGF‑D, which bind to the cell surface tyrosine kinase receptor VEGF receptor‑3 (VEGFR‑3); C‑C motif chemokine receptor 7 (CCR7); neuropilin (NRP)1 and NRP2; and semaphorin 3E (SEMA3E). Furthermore, we assessed microvessel density (MVD) and lymphatic vessel density (LVD) to demonstrate the correlation between these factors and regional LN metastasis, with respect to the clinicopathological features. Finally, we analyzed the correlation between these proteins and overall or disease‑free survival, in order to demonstrate their prognostic value. Univariate analysis revealed a significant association between LN metastasis and the expression levels of VEGF‑C, VEGFR‑3, CCR7, NRP1, and SEMA3E, as well as LVD, in SCC cells. In contrast, multivariate analysis identified associations between LN metastasis and NRP1 expression, as well as between LN metastasis and LVD; however, no correlation was found between LN metastasis and the expression levels of the other proteins. The expression levels of VEGF‑C, VEGFR‑3, NRP1, and SEMA3E, as well as LVD, were correlated with disease‑free survival time. These results indicate that LN metastasis is associated with poor survival in SCC. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in SCC of the tongue, whereas the expression of VEGF‑C, VEGFR‑3, CCR7, and SEMA3E are non‑independent predictive factors.
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Hani
H
Al-Shareef
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Shin-Ichiro
SI
Hiraoka
Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Noriaki
N
Tanaka
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Yosuke
Y
Shogen
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Atsushi-Doksa
AD
Lee
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Sanam
S
Bakhshishayan
First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Mikihiko
M
Kogo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D039942:Neuropilin-1 / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000235:genetics*; D039961:Semaphorins / Q000096:biosynthesis / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics*
D014408:Biomarkers, Tumor; C515370:CCR7 protein, human; D054400:Receptors, CCR7; C494123:SEMA3E protein, human; D039961:Semaphorins; D042582:Vascular Endothelial Growth Factor C; D039942:Neuropilin-1; D040321:Vascular Endothelial Growth Factor Receptor-3
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