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PTTG1 cooperated with GLI1 leads to epithelial-mesenchymal transition in esophageal squamous cell cancer.

ABSTRACT: Pituitary tumor-transforming gene-1 (PTTG1) could acquire its metastasis-promoting effects via inducing epithelial-mesenchymal transition (EMT). However, its role and mechanism in EMT in esophageal squamous cell cancer (ESCC) had not been clearly elucidated. Here, we demonstrated that PTTG1 was overexpressed in ESCC cell lines and tissues especially those with lymph node metastasis. Down regulation of PTTG1 levels dampened the ESCC cells invasion, migration, proliferation ability and colony formation in vitro and inhibited the growth of mouse xenograft model of ESCC cells in vivo. In addition, our in vitro and in vivo experiments consistently showed that decreased PTTG1 led to the inhibition of EMT process. Glioma-associated oncogene homolog1 (GLI1), a key factor in HH-GLI signaling pathway, was also overexpressed in ESCC cells and tissues. Mechanistic studies demonstrated that decreased PTTG1 mitigated the expression levels of GLI1 in vitro and in vivo and ChIP assay also indicated that PTTG1 cooperated with GLI1 by binding to its promoter. Furthermore, overexpression of GLI1 rescued the EMT inhibited by down regulation of PTTG1 in vitro. Together, these data suggested that PTTG1 promoted the invasion ability of ESCC cells via EMT, more important, PTTG1 participated in EMT via activating the expression of GLI1 in ESCC. PTTG1 could be a candidate biomarker for defining ESCC metastasis and useful target for therapy.

SUBMITTER: Feng W

PROVIDER: S-EPMC5696190 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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PTTG1 cooperated with GLI1 leads to epithelial-mesenchymal transition in esophageal squamous cell cancer.

Feng Wang W Xiaoyan Xuan X Shenglei Li L Hongtao Liu L Guozhong Jiang J

Oncotarget 20170927 54

Pituitary tumor-transforming gene-1 (PTTG1) could acquire its metastasis-promoting effects via inducing epithelial-mesenchymal transition (EMT). However, its role and mechanism in EMT in esophageal squamous cell cancer (ESCC) had not been clearly elucidated. Here, we demonstrated that PTTG1 was overexpressed in ESCC cell lines and tissues especially those with lymph node metastasis. Down regulation of PTTG1 levels dampened the ESCC cells invasion, migration, proliferation ability and colony form ...[more]

PMID: 29190924

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Project description:ObjectiveThis article investigates the role of Transgelin (TAGLN) in the epithelial-mesenchymal transition (EMT) of esophageal squamous cell carcinomas (ESCC) and its possible mechanism of inhibiting the invasion of these cancers.MethodsTissue specimens and clinical information of patients with ESCC were collected to analyze the relationship between Transgelin expression level and prognosis of patients with ESCC. Transgelin siRNA was used to knock down Transgelin expression. The expression of Transgelin in Eca-109 and KYSE-150 cells was overexpressed by Transgelin-overexpressing plasmid. The effects of Transgelin overexpression and knockdown on the proliferation of Eca-109 and KYSE-150 cells were examined by Transwell chamber, scratch assay, and CCK-8 cell activity assay. RT-PCR and Western blot were used to detect the effect of Transgelin overexpression or knockdown on the mRNA and protein expressions of E-cadherin and Vimentin. TCGA data were used to analyze Transgelin co-expressed genes and further study the GO and KEGG enrichment analysis results under the influence of Transgelin.ResultsThe expression of Transgelin was low in ESCC, and its expression level was positively correlated with the prognosis of patients with ESCC. The targeted Transgelin siRNA and Transgelin-overexpressing plasmid can effectively regulate the expression of Transgelin mRNA and protein in Eca-109 and KYSE-150 cells. After overexpression of Transgelin, the invasion and proliferation abilities of Eca-109 and KYSE-150 cells were significantly decreased compared with those of the control group (P < 0.05). However, Transgelin knockdown could promote the proliferation, migration, and invasion of ESCC cells. The overexpression of Transgelin inhibits EMT in ESCC. With the increase of Transgelin expression in Eca-109 and KYSE-150 cells, the expression of E-cadherin increased, while the expression of Vimentin decreased, and the difference was statistically significant (P < 0.05).ConclusionTransgelin can inhibit the malignant progression of ESCC by inhibiting the occurrence of EMT.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Due to its high morbidity and mortality rates, it is urgent to find a molecular target that contributes to esophageal carcinogenesis and progression. In this research, we aimed to investigate the functions of Latent transforming growth factor β binding protein 1(LTBP1) in ESCC progression and elucidate the underlying mechanisms.MethodsThe tandem mass tag-based quantitative proteomic approach was applied to screen the differentially expressed proteins (DEPs) between 3 cases of ESCC tumor samples and paired normal tissues. Then the DEPs were validated in human ESCC tissues using western blot assays and GEPIA database respectively. The expression level of LTBP1 was detected in 152 cases of ESCC tissues and paired normal tissues. Loss-of-function assays were performed to detect the function of LTBP1 in vivo and in vitro. Immunofluorescence and Western blot assays were used to detect the expression of apoptosis, epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) markers.ResultsA total of 39 proteins were screened to be up-regulated (ratio > 2.0) in all three ESCC tissues. The results of immunohistochemistry assays indicated that the expression level of LTBP1 was higher in ESCC tissues than that in paired normal tissues (p < 0.001). Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC (p = 0.002). Down-regulation of LTBP1 inhibited the invasion and migration as well as metastatic abilities in vitro and in vivo. It was also observed the down-regulation of LTBP1 not only decreased the mesenchymal phenotypes but also inhibited TGFβ-induced EMT in ESCC cells. We further found that down-regulation of LTBP1 enhanced ESCC cells' sensitivity to 5-FU treatment. Inhibition of LTBP1 expression could also attenuate induction of CAFs transformation and restrain fibroblast express fibronectin (FN1) in ESCC cells.ConclusionOverexpression of LTBP1 was associated with lymph node metastasis in ESCC. Our results indicated that LTBP1 not only increased the malignant behaviors of ESCC cells but also induced EMT and CAFs transformation. Our studies suggested an oncogenic role of LTBP1 in ESCC progression and it may serve as a potential therapeutic target for ESCC patients.

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PTTG1 cooperated with GLI1 leads to epithelial-mesenchymal transition in esophageal squamous cell cancer.

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PTTG1 cooperated with GLI1 leads to epithelial-mesenchymal transition in esophageal squamous cell cancer.

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