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Abstract
The membrane-cytoskeleton link organizer ezrin may be the most “dramatic” tumor marker, being strongly over-expressed in nearly one-third of human malignancies. However, the molecular mechanisms of aberrant ezrin expression still need to be clarified. Ezrin, encoded by the VIL2 gene, has two transcript variants that differ in the transcriptional start site (TSS): V1 and V2. Both V1 and V2 encode the same protein. Here, we found that 12-O-tetradecanoylphorbol-13-acetate (TPA) induced over-expression of human VIL2 in esophageal squamous cell carcinoma (ESCC) cells. Furthermore, VIL2 V1 but not V2 was up-regulated after TPA stimulation in a time-dependent manner. AP-1 and Sp1 binding sites within the promoter region of VIL2 V1 acted not only as basal transcriptional elements but also as a composite TPA-responsive element (TRE) for the transcription of VIL2 V1. TPA stimulation enhanced c-Jun and Sp1 binding to the TRE via activation of the ERK1/2 pathway and increased protein levels of c-Jun, c-Fos, and Sp1, resulting in over-expression of VIL2 V1, whereas the MEK1/2 inhibitor U0126 blocked these events. Finally, we showed that TPA promoted the migration of ESCC cells whereas MEK1/2 inhibitor or ezrin silencing could partially inverse this alteration. Taken together, these results suggest that TPA is able to induce VIL2 V1 over-expression in ESCC cells by activating MEK/ERK1/2 signaling and increasing binding of Sp1 and c-Jun to the TRE of the VIL2 V1 promoter, and that VIL2 is an important TPA-induced effector.
Highlights
Ezrin is a member of the Ezrin-Radixin-Moesin (ERM) cytoskeleton-associated protein family, which primarily acts as physical and functional links between the plasma membrane and cytoskeleton [1,2]
We previously showed that the overexpression of ezrin in esophageal squamous cell carcinoma (ESCC) may be involved in the growth and invasiveness of ESCC cells and ezrin expression can serve as a biomarker that predicts the prognosis of ESCC patients [17,18]
Results of qRT-polymerase chain reaction (PCR) assay revealed that TPA showed the greatest induction of the transcription of VIL2 V1 among those inducible factors, whereas it did not affect the expression of VIL2 variant 2 (V2) (Fig 1C)
Summary
Ezrin is a member of the Ezrin-Radixin-Moesin (ERM) cytoskeleton-associated protein family, which primarily acts as physical and functional links between the plasma membrane and cytoskeleton [1,2]. 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, could lead to the malignant transformation of human embryonic esophageal mucosa cells to ESCC cells, in which ezrin was overexpressed obviously, suggesting TPA might be an inducer of VIL2 overexpression in ESCC cells [23,24].
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