RESUMEN
Background: The zinc-finger transcription factor Sal-like protein 4 (SALL4) plays a pivotal role in tumor invasion and metastasis. Here, we investigated the clinicopathological significance of SALL4 overexpression in cervical squamous cell carcinoma (SCC) of the uterine cervix. Methods: SALL4 immunohistochemical staining was performed on cervical SCC specimens from 129 patients, as well as 98 cases of cervical squamous intraepithelial lesion (LSIL and HSIL) and 29 normal cervix samples. SALL4 immunofluorescence staining was performed in CaSki and SiHa cervical cancer cells. Statistical analyses were applied to evaluate correlations between SALL4 overexpression and clinicopathological features of SCC patients. Survival rates were calculated using the Kaplan-Meier method, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazard models. Results: SALL4 protein showed mainly nuclear staining in cervical cancer cells. Strong diffuse SALL4 staining was frequently seen in cervical cancer compared with normal tissues. SALL4 expression was significantly higher in cervical cancers than in LSIL, HSIL, and normal cervical epithelia. SALL4 overexpression was positively correlated with poor differentiation, late-stage, and lymph node metastasis. Moreover, the 5-year survival rate of early-stage cervical cancer patients with high SALL4 expression was significantly lower than patients with low SALL4 expression. Multivariate analysis suggested that SALL4 protein expression is an independent risk factor for survival in SCC. Conclusions: SALL4 plays an important role in SCC progression. High-level SALL4 expression is an independent prognostic factor of poor outcomes in SCC.
RESUMEN
Cervical cancer is the third most common cancer in females worldwide. The treatment options for advanced cervical cancer are limited, leading to high mortality. Ezrin is a membrane-cytoskeleton-binding protein recently reported to act as a tumor promoter, and we previously indicated that the aberrant localization and overexpression of Ezrin could be an independent effective biomarker for prognostic evaluation of cervical cancers. In this study, we identified Ezrin as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in cervical cancer. Ezrin knock-down inhibited anchorage-independent growth, cell migration, and invasion of cervical cancer cell lines in vitro and in vivo. EMT was inhibited in Ezrin-depleted cells, with up-regulation of E-cadherin and Cytokeratin-18 (CK-18) and down-regulation of mesenchymal markers. Ezrin knock-down also induced Akt phosphorylation. These results implicate Ezrin as an EMT regulator and tumor promoter in cervical cancer, and down-regulation of Ezrin suppressed cervical cancer progression, possibly via the phosphoinositide 3-kinase/Akt pathway. Furthermore, the expression pattern of Ezrin protein was closely related with the lymphovascular invasion status of cervical cancer by immunohistochemistry, and the survival analysis revealed that the cervical cancer patients with the perinuclear Ezrin expression pattern had longer survival time than those with the cytoplasmic Ezrin expression pattern. Ezrin thus represents a promising target for the development of novel and effective strategies aimed at preventing the progression of cervical cancer.
