12-O-Tetradecanoylphorbol-13-Acetate Induces Up-Regulated Transcription of Variant 1 but Not Variant 2 of VIL2 in Esophageal Squamous Cell Carcinoma Cells via ERK1/2/AP-1/Sp1 Signaling.
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.
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Institute of Oncologic Pathology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
Xiao-Dan
XD
Zhang
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
Jian-Jun
JJ
Xie
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Institute of Oncologic Pathology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
Lian-Di
LD
Liao
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
Lin
L
Long
Department of Experimental Animal Center, Medical College of Shantou University, Shantou 515041, P. R. China.
Yang-Min
YM
Xie
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
En-Min
EM
Li
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China; Institute of Oncologic Pathology, Medical College of Shantou University, Shantou 514041, Guangdong, P.R. China.
Li-Yan
LY
Xu
D017398:Alternative Splicing; D001665:Binding Sites; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018387:Codon, Initiator; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015854:Up-Regulation; D000099149:Ezrin
D002070:Butadienes; D018387:Codon, Initiator; D003598:Cytoskeletal Proteins; D004247:DNA; D009570:Nitriles; D013755:Tetradecanoylphorbol Acetate; D000099149:Ezrin; C113580:U 0126