Role of Integrin ß1 in the progression and chemo-resistance of esophageal squamous cell carcinoma.

Objective: Integrins have been shown to play an important role in the tumorigenesis of many cancers. In this work, we aimed to explore the expression and clinical value of Integrin α5ß1 in esophageal squamous cell carcinoma (ESCC), and the effect of integrin ß1 on the development and chemo-resistance of ESCC cells. Methods: The expression profiling of integrins was analyzed in the mRNA expression dataset of ESCC. The expression of Integrin α5ß1 in 278 cases of ESCC tissues and 62 cases of paracancerous tissues was detected by immunohistochemistry (IHC). The association between the expression of Integrin α5ß1 and the survival of ESCC patients was analyzed by Kaplan-Meier analysis. The effect of Integrin ß1 on the proliferation, migration, and invasion of ESCC cells was examined by MTS, Transwell migration, and Transwell invasion assay. The effect of Integrin ß1 and L1 cell adhesion molecule (L1CAM) on cisplatin resistance was detected by MTS and the signal pathways involved were analyzed by Western blotting. Results: Integrin ß1 and Integrin α5 were significantly up-regulated in ESCC. High expression of Integrin ß1 was also related to worse overall survival of ESCC patients and patients with low levels of both Integrin ß1 and Integrin α5 showed the shortest survival. Results of IHC revealed that Integrin α5ß1 was up-regulated in ESCC and its high expression was associated with poor prognosis and could serve as an independent prognostic factor. siRNA-mediated Integrin ß1 silencing or antibody blocking restrained the proliferation, migration, and invasion of ESCC cells. Simultaneous knockdown of Integrin ß1 and L1CAM reduced the cisplatin resistance of ESCC cells. Further studies showed that knockdown of Integrin ß1 and L1CAM suppressed the activity of Akt signaling with or without cisplatin treatment. Moreover, dual high expression of Integrin ß1 and L1CAM was related to worse overall survival of ESCC patients treated with preoperative chemotherapy. Conclusion: Integrin α5ß1 was up-regulated in ESCC and could be used as a new prognostic indicator for ESCC patients. In addition, Integrin ß1 was involved in the proliferation, invasion, and chemo-resistance of ESCC cells.

Diagnostic and prognostic value of serum L1-cell adhesion molecule in esophageal squamous cell carcinoma.

OBJECTIVE: L1 cell adhesion molecule (L1CAM) has been found to be dysregulated in several types of human cancers. Here, we aimed to determine the level of soluble L1CAM in serum of patients with esophageal squamous cell carcinoma (ESCC). METHODS: Serum levels of L1CAM were determined by an enzyme-linked immunosorbent assay (ELISA) in 191 patients with ESCC and 94 normal controls. Receiver operating characteristics (ROC) was employed to calculate diagnostic accuracy. Cumulative survival time was calculated by the Kaplan-Meier method and analyzed by the logrank test. RESULTS: Levels of L1CAM were significantly lower in all ESCC patients than in normal controls (P < 0.001). Detection of serum L1CAM provided a sensitivity of 28.3%, a specificity of 90.4% and an area under the curve (AUC) of 0.644 (95% CI: 0.579-0.710) in diagnosing ESCC. Similar results were observed in the diagnosis of early-stage ESCC (26.2% sensitivity, 90.4% specificity, and an AUC of 0.629). Moreover, decreased level of L1CAM was correlated with depth of tumor invasion (P < 0.05). Kaplan-Meier analysis showed that lower serum L1CAM level was significantly related to shorter overall survival time (P = 0.036) and disease-free survival time (P = 0.021) of ESCC patients. CONCLUSIONS: Our study demonstrated that serum L1CAM might serve as a potential biomarker for the diagnosis and prognosis of ESCC.

L1CAM drives oncogenicity in esophageal squamous cell carcinoma by stimulation of ezrin transcription.

L1 cell adhesion molecule (L1CAM) is highly expressed in various types of human cancers, displaying yet unknown molecular mechanisms underlying their oncogenic potential. Here, we found that L1CAM expression was significantly increased in esophageal squamous cell carcinoma (ESCC; n = 157) lesions compared with non-cancerous tissues. High tumorous L1CAM expression significantly correlated with reduced overall survival. Experimentally, L1CAM knockdown led to decreased cell growth, migration, and invasiveness in vitro, whereas overexpression of L1CAM showed the opposite effect. In nude mice, L1CAM depletion attenuated tumorigenesis and ability to penetrate the tissues surrounding ESCC cells. Gene set enrichment analysis (GSEA) and SubpathwayMiner analysis on gene expression profiles (microarray data on ESCC tissues, GSE53625; cDNA microarray data on L1CAM-knockdown ESCC cell line, GSE86268) suggested that L1CAM-co-expression genes were related to cell motility, cell proliferation, and regulation of actin cytoskeleton, validating the above experimental findings. Further mechanistical analysis showed that L1CAM upregulated the expression of the cytoskeletal protein ezrin via activating integrin ß1/MAPK/ERK/AP1 signaling and thus led to the malignant phenotypes of ESCC cells. Together, our findings suggest that L1CAM may be employed as a valuable prognosis marker and a therapeutic target for ESCC patients and that L1CAM promotes ESCC tumorigenicity by upregulating ezrin expression. KEY MESSAGES: L1CAM promotes growth and invasiveness of ESCC cells in vitro and in vivo. L1CAM upregulates the expression of ezrin by integrin α5ß1/MAPK/ERK/AP1 pathway. Ezrin is a key downstream effector in the L1CAM-promoted malignant phenotypes. High expression levels of both L1CAM and ezrin significantly correlated with reduced overall survival. Nuclear L1CAM is an independent prognosis marker for esophageal squamous cell carcinoma.

Integrin α5 promotes tumor progression and is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma.

The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. The expression and function of integrin α5 in esophageal squamous cell carcinoma (ESCC) are not clear. Here, by using tissue microarrays and immunohistochemical method, integrin α5 expression was retrospectively evaluated in 147 samples of human ESCC. Results showed that expression of integrin α5 was heterogeneous and varied from negative to intense expression in a membrane and cytoplasmic distribution manner. High expression of integrin α5 was significantly correlated with lymph node metastasis (P = .042) and tumor size (P = .042). Kaplan-Meier analysis revealed that high expression of integrin α5 was related to poor overall survival of ESCC patients (P = .018). Multivariate analysis suggested that integrin α5 expression status was an independent prognostic factor for ESCC (P = .003). Moreover, integrin α5 expression was associated with the survival of patients with lymph node metastasis (P = .020), but did not influence the survival of patients without lymph node metastasis. Finally, we found that RNAi-mediated knockdown of integrin α5 led to decreased growth, migration, and invasion of ESCC cells. Combined, integrin α5 might play important roles in the progression of ESCC. Integrin α5 is a novel biomarker to predict the prognosis of ESCC patients.