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Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPAR?-Akt signaling pathway at the early stage of carcinogenesis.

ABSTRACT: The poor prognosis of esophageal squamous cell carcinoma (ESCC) emphasizes the urgent need to better understand the carcinogenesis and develop prevention strategies. Previous studies have highlighted the potential of using Vitamin E (tocopherols) for cancer chemoprevention, but the preventive activity of ?-Tocopherol against ESCC remains to be elucidated. Our data showed that early-stage supplementation with ?-Tocopherol significantly prevented esophageal carcinogenesis induced by N-nitrosomethylbenzylamine (NMBA) in ESCC rat model. In the Het-1A cell model, ?-Tocopherol markedly suppressed cell proliferation, promoted cell cycle G2-phase arrest and increased apoptosis. Gene microarray and proteins array analysis indicated that Akt signaling was a potential target for ?-Tocopherol. We further demonstrated that ?-Tocopherol increased the expression of PPAR? and its downstream tumor suppressor PTEN. Knockdown of PPAR? activated Akt signaling transduction, whereas this process was attenuated by the presence of ?-Tocopherol and PPAR? agonist Rosiglitazone. In contrast, the effect of ?-Tocopherol on Akt inhibition was not observed in established tumors, neither in cancerous cell lines which constitutively expressed higher levels of PPAR?. These results were closely correlated with the ineffectiveness of ?-Tocopherol in the late stage of ESCC carcinogenesis. Taken together, our study suggested that ?-Tocopherol may serve as a PPAR? agonist for the chemoprevention of esophageal cancer.

SUBMITTER: Xu M

PROVIDER: S-EPMC5707070 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPARγ-Akt signaling pathway at the early stage of carcinogenesis.

Xu Miao M Yang Hui H Zhang Qiannan Q Lu Ping P Feng Yongquan Y Geng Xue X Zhang Lishi L Jia Xudong X

Oncotarget 20170930 56

The poor prognosis of esophageal squamous cell carcinoma (ESCC) emphasizes the urgent need to better understand the carcinogenesis and develop prevention strategies. Previous studies have highlighted the potential of using Vitamin E (tocopherols) for cancer chemoprevention, but the preventive activity of α-Tocopherol against ESCC remains to be elucidated. Our data showed that early-stage supplementation with α-Tocopherol significantly prevented esophageal carcinogenesis induced by <i>N</i>-nitro ...[more]

PMID: 29221176

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Project description:ObjectiveOur previous study suggested cyclin-dependent kinase-like 3 (CDKL3) acts as a new oncogene in esophageal squamous cell carcinoma (ESCC) cell line TE-1. However, the molecular mechanisms and biological effects of CDKL3 in ESCC remain unknown. In the present study, we aimed to explore the clinical significance of CDKL3 in ESCC and how CDKL3 regulates the malignant behavior of ESCC.MethodsESCC samples were stained by immunohistochemical staining (IHC) and analyzed for the expression of CDKL3. The functions of CDKL3 on proliferation, apoptosis, migration, invasion, and colony formation were investigated by celigo assay, MTT assay, colony formation, caspase 3/7 activity analysis, transwell migration and invasion assay, respectively. A transplanted tumor model was established to study the functions of FLVCR1 on the tumorigenesis of ESCC cells. Microarray analysis was utilized to identify the CDKL3-regulated genes in ESCC cells.ResultsESCC tumor tissues possessed a significantly higher expression of CDKL3 and autophagy-related gene 5 (ATG5) than matched adjacent normal tissues. The high expressions of CDKL3 were positively associated with the tumor-node-metastasis (TNM) stage and Ki67. Upregulated ATG5 expression was positively correlated with male, advanced tumor (T) stage, and TNM stage. Kaplan-Meier analysis showed that ESCC patients with higher expression of CDKL3 or ATG5 had a shorter overall survival. The worst prognosis was recognized in patients with both high manifestations of CDKL3 and ATG5. Time-dependent receiver operating characteristic (ROC) curve was established to reveal that the combination of CDKL3, ATG5, and TNM stage-based model had better prognostic accuracy than TNM stage. Moreover, CDKL3 knockdown markedly repressed cell growth and aggressivity in vitro and in vivo. Mechanistically, ATG5 was confirmed as a downstream gene involved in the pro-oncogenic function of CDKL3.ConclusionCDKL3 can be utilized as an independent poor prognostic marker in ESCC patients. Furthermore, CDKL3 may promote tumor profession, invasion, metastasis, and prohibit tumor apoptosis partly by ATG5 activation.

Project description:ObjectiveEndothelial cell-specific molecule 1 (ESM1) has been implicated as an oncogene in several types of cancer. However, the potential role of ESM1 in esophageal carcinogenesis (ESCA)/esophageal squamous cell carcinoma (ESCC) is still unclear.MethodsThe expression, function, and survival data of ESM1 were observed using a bioinformatics approach. Subsequently, the expression level of ESM1 in surgical esophageal tumors and adjacent normal tissues was detected by qRT-PCR and immunofluorescence. We further revealed protein expression by immunohistochemistry (IHC), which is related to the prognosis of patients with ESCC using survival analysis. In vitro, knockdown of ESM1 in KYSE150 and KYSE510 cell lines, colony formation assays, wound healing assays, and Transwell assays were performed.ResultsESM1 is significantly elevated in 12 of 20 types of human cancer. ESM1 is highly expressed in tumor tissue compared with adjacent normal tissue and was identified as a hub gene in ESCA. Clinical outcome endpoints of overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) curves showed that patients whose ESM1 expression was high had a lower clinical survival rate. The ESM1 high-expression group has a certain correlation with clinical stage and grade. The IHC of ESM1 further demonstrated that the higher the expression was, the worse the N classification and pTNM stage in patients with ESCC, which had a distinctly poorer overall 5-year survival rate. Univariate analysis showed that age, N classification, pTNM stage, and ESM1 expression were all prognostic factors, although multivariate Cox regression analysis showed that only pTNM stage was an independent prognostic factor. In vitro, silencing ESM1 suppressed the proliferation, migration, and invasion of KYSE150 and KYSE510 cells.ConclusionsESM1 is a hub gene in the initiation and progression of ESCA/ESCC that promotes the proliferation, migration, and invasion of esophageal cancer cells and may be a promising therapeutic target and prognostic indicator.

Dataset Information

Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPAR?-Akt signaling pathway at the early stage of carcinogenesis.

Publications

Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPARγ-Akt signaling pathway at the early stage of carcinogenesis.

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