1272

CNTN1

contactin 1;CNTN1;contactin 1

contactin-1|glycoprotein gP135|neural cell surface protein F3

12q11-q12

protein-coding

Vascular endothelial growth factor C (VEGF-C) is a key regulator of angiogenesis and lymphangiogenesis. VEGF-C is also implicated in the development of esophageal cancer. We investigated the mRNA levels of VEGF-C and its receptors in 38 esophageal squamous cell carcinoma specimens (ESCCs) and matched adjacent normal esophageal tissues via real-time PCR. The mRNA levels of VEGF-C, VEGFR-2 and VEGFR-3 were significantly upregulated in ESCCs versus respective side normal tissues. To explore the influence of VEGF-C on esophageal cancer progression, the expression of VEGF-C was manipulated in esophageal cancer cell lines TE-1 and Eca-109. VEGF-C transcription, translation and secretion were significantly enhanced in cells stably transfected with a VEGF-C overexpression vector or attenuated in VEGF-C shRNA-transfected cell lines. In vitro, TE-1 cells stably transfected with a VEGF-C overexpression vector exhibited an increased rate of cell proliferation, migration and focus formation, whereas knockdown of VEGF-C inhibited cell proliferation, migration and focus formation. Similar results were obtained for Eca-109 cells. VEGF-C mediated biological function through transcription of CNTN-1, which is implicated in tumor invasion and metastasis. The expression of VEGF-C was correlated with that of CNTN-1 and cell proliferation and migration induced by VEGF-C were reversed by silencing of CNTN-1. In addition, nude mice inoculated with VEGF-C shRNA-transfected cells exhibited a significantly decreased tumor size in vivo via reduced VEGFR-2 and VEGFR-3 phosphorylation and microvessel formation. VEGF-C upregulation may be involved in esophageal tumor progression. Vector-based RNA interference (RNAi) targeting VEGF-C is a potential therapeutic method for human esophageal carcinoma.

Numerous genetic changes are associated with cancer cell metastasis and invasion. In search for key regulators of invasion and metastasis, a panel of lung cancer cell lines with different invasive ability was screened. The gene for contactin-1 was found to play an essential role in tumor invasion and metastasis. Suppression of contactin-1 expression abolished the ability of lung adenocarcinoma cells to invade Matrigel in vitro as well as the polymerization of filamentous-actin and the formation of focal adhesion structures. Furthermore, knockdown of contactin-1 resulted in extensive inhibition of tumor metastasis and in increased survival in an animal model. RhoA but not Cdc42 or Rac1 was found to serve a critical role in contactin-1-mediated invasion and metastasis. Contactin-1-specific RNA interference resulted in loss of metastatic and invasive capacity in both in vitro and in vivo models. This loss was overturned by constitutive expression of the active form of RhoA. Contactin-1 was differentially expressed in tumor tissues, and its expression correlated with tumor stage, lymph node metastasis, and patient survival. Contactin-1 is proposed to function importantly in the invasion and metastasis of lung adenocarcinoma cells via RhoA-mediated mechanisms.

The contactin 1 (CNTN1) gene exerts oncogenelike activities and its expression has been linked to several human malignancies. In this study, a possible association between CNTN1 expression and clinicopathological parameters and clinical outcomes in patients with oral squamous cell carcinoma (OSCC) was examined. CNTN1 protein expression was evaluated by immunohistochemistry in OSCC tissues of 45 patients. For the immunohistochemical assessment of CNTN1 expression, the cytoplasmic staining labeling index was analyzed using a semiquantitative score. The association between CNTN1 protein levels and clinicopathological factors was analyzed using the Mann-Whitney U test for categorical variables and the Kruskal-Wallis test for continuous variables. The effects of CNTN1 expression on overall and disease-free survival were assessed by using univariate survival analysis. The transcript levels of CNTN1 were detected in OSCC cell lines. In addition, specific siRNA against CNTN1 was applied to investigate the effect exerted by CNTN1 ablation on OSCC cell lines by proliferation and invasion assays in vitro. During follow-up, 16 patients (35.56%) had succumbed to OSCC; the median follow-up of patients was 5.0 years (range, 0.2-8.3). A high expression of CNTN1 was markedly associated with the regional lymph node metastasis of patients with OSCC (P=0.006). CNTN1 expression was significantly associated with overall survival of patients with OSCC (P=0.032; log-rank test) and disease-free survival of patients with OSCC (P=0.038; log-rank test). In addition, CNTN1 ablation notably suppressed the invasion potential of OSCC cell lines, but there was no significant change in the proliferation of OSCC cell lines by CNTN1 knockdown in vitro. The study supports CNTN1 as a novel predictor of regional lymph node metastasis in patients with OSCC and a prognostic marker for OSCC in patients.