Abstract
Human Dachshund homologue 1 (DACH1) is a major component of the Retinal Determination Gene Network. Loss of DACH1 expression was found in breast, prostate, lung, endometrial, colorectal and hepatocellular carcinoma. To explore the expression, regulation and function of DACH1 in human esophageal cancer, 11 esophageal cancer cell lines, 10 cases of normal esophageal mucosa, 51 cases of different grades of dysplasia and 104 cases of primary esophageal squamous cancer were employed. Methylation specific PCR, immunohistochemistry, western blot, flow cytometry, small interfering RNAs, colony formation techniques and xenograft mice model were used. We found that DACH1 expression was regulated by promoter region hypermethylation in esophageal cancer cell lines. 18.8% (6 of 32) of grade 1, 42.1% (8 of 19) of grade 2 and grade 3 dysplasia (ED2,3), and 61.5% (64 of 104) of esophageal cancer were methylated, but no methylation was found in 10 cases of normal esophageal mucosa. The methylation was increased in progression tendency during esophageal carcinogenesis (P<0.01). DACH1 methylation was associated with poor differentiation (P<0.05) and late tumor stage (P<0.05). Restoration of DACH1 expression inhibited cell growth and activated TGF-β signaling in KYSE150 and KYSE510 cells. DACH1 suppressed human esophageal cancer cell tumor growth in xenograft mice. In conclusion, DACH1 is frequently methylated in human esophageal cancer and methylation of DACH1 is involved in the early stage of esophageal carcinogenesis. DACH1 expression is regulated by promoter region hypermethylation. DACH1 suppresses esophageal cancer growth by activating TGF-β signaling.
Highlights
Esophageal cancer is the fifth most malignant disease and has been ranked as the fourth leading cause of cancer related deaths in China. [1] Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal cancer, and accounts for approximately 90% of esophageal cancer cases in the northern and central China. [2] Despite the development of multimodal therapies, the 5 year overall survival remains below 20%. [3] The mechanisms of esophageal carcinogenesis remain unclear
Dachshund homolog 1 (DACH1) expression was regulated by promoter region hypermethylation in human colorectal and hepatocellular carcinoma. [12,13] To explore the regulation of DACH1 in ESCC, the expression and the methylation status of DACH1 were detected by RT-PCR and Methylation Specific PCR (MSP) in esophageal cancer cell lines
Loss of DACH1 expression was found in KYSE150, KYSE510, TE1 and TE3 cells, reduced DACH1 expression was appeared in TE8 cells, and expression of DACH1 was detected in KYSE30, KYSE70, KYSE140, KYSE180, KYSE450 and KYSE410 cells
Summary
Esophageal cancer is the fifth most malignant disease and has been ranked as the fourth leading cause of cancer related deaths in China. [1] Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal cancer, and accounts for approximately 90% of esophageal cancer cases in the northern and central China. [2] Despite the development of multimodal therapies, the 5 year overall survival remains below 20%. [3] The mechanisms of esophageal carcinogenesis remain unclear. [3] The mechanisms of esophageal carcinogenesis remain unclear. Multiple genetic and epigenetic alterations were regarded as important factors for developing esophageal cancer [4,5,6]. Reduction of DACH1 expression was associated with poor prognosis in breast, prostate, lung, endometrial, colorectal and hepatic cancer. [7,8,9,10,11,12,13] The expression of DACH1 was regulated by promoter region hypermethylation in endometrial, colorectal and hepatocellular cancer. [13] While the epigenetic changes and the function of DACH1 in human ESCC remain unclear. We mainly analyzed the epigenetic changes and the mechanism of DACH1 on esophageal carcinogenesis
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