Overexpression of SIP1 and Downregulation of E-cadherin Predict Delayed Neck Metastasis in Stage I/II Oral Tongue Squamous Cell Carcinoma After Partial Glossectomy

Abstract

Patients with clinical stage I/II (T1-2N0M0) oral tongue squamous cell carcinoma (TSCC) usually undergo partial glossectomy alone. However, 14-48% of them develop delayed neck metastasis (DNM), which may lead to an unfavorable course. Recently epithelial-to-mesenchymal transition (EMT) has been thought to play a crucial role in cancer metastasis. The present study aimed to examine the associations of EMT-involved molecular factors and clinicopathological factors with DNM in stage I/II TSCC. mRNA expression levels of E-cadherin and its transcriptional repressors (snail, SIP1, and twist) in 7 head and neck squamous cell carcinoma (HNSCC) cell lines were evaluated by quantitative real-time PCR. Clinicopathological parameters and immunohistochemical expressions of E-cadherin and its repressors were examined in surgical specimens of 37 stage I/II TSCC patients who underwent partial glossectomy alone. In HNSCC cells, E-cadherin expression was inversely correlated with SIP1 expression (P = 0.023). Univariate analysis of immunohistochemistry showed that overexpression of SIP1 and loss of E-cadherin were significantly correlated with DNM, although no inverse correlation was found between E-cadherin and its repressors. Multiple logistic regression analysis including clinicopathological and molecular factors revealed that overexpression of SIP1 (P = 0.005), loss of E-cadherin (P = 0.046), and vascular invasion (P = 0.024) were independently correlated with DNM. These results suggest that development of DNM in stage I/II TSCC is closely related to induction of EMT in primary tumor cells. Especially, SIP1 and E-cadherin are considered to be the possible markers for selecting patients at high risk of DNM.