title: Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2.
abstract: Stat3 alters the expression of its downstream genes and is associated with tumor invasion and metastasis in several human cancers. Its role in esophageal squamous cell carcinoma (ESCC) has not been well characterized. We examined the tumor sections of 100 cases of ESCC by immunohistochemistry and observed significant overexpression of Stat3 in the cytoplasm of 89% of ESCC cells and of phosphorylated Stat3 (p-Stat3) in the nuclei of 71% of ESCC when compare with normal esophageal mucosa (72%, p = 0.02; and 31%, p = 0.001). Overexpression of Stat3 and p-Stat3 positively correlated with that of matrix metalloproteinase-2 (MMP2), a known regulator for cell migration, in 65% of ESCC while only 26% shown in benign esophageal mucosa. To further investigate the association of Stat3 with tumor metastasis in vitro, invasion of EC-1 cells (a human ESCC cell line) were investigated with Boyden chambers. The results showed that transfection of Stat3 not only promoted invasion of EC-1 cells but also significantly induced MMP2 expression in a dose-dependent manner. In contrast, suppressing expression of endogenous Stat3 mRNA and protein by Stat3 siRNA significantly reduced EC-1 cell invasion and MMP2 expression. A high-affinity Stat3-binding element was localized to the positions of 648-641 bp (TTCTCGAA) in the MMP2 promoter with electrophoretic mobility shift assay. Our results suggest that Stat3, p-Stat3, and MMP2 were overexpressed in ESCC and associated with invasion of ESCC; and Stat3 up-regulated expression of MMP2 in ESCC through directly binding to the MMP2 promoter.
authors.affiliation: Department of Pathology, The First Affiliated Hospital and Key Laboratory of Tumor Pathology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China.
authors.forename: Xaioyan
authors.initials: X
authors.lastname: Xuan
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Lou
authors.forename: Xianzhao
authors.initials: X
authors.lastname: Zheng
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Hongliu
authors.initials: H
authors.lastname: He
authors.forename: Qingru
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000503:physiopathology; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2