Abstract
ObjectivesThis study explored the expression and function of Slug in human extrahepatic hilar cholangiocarcinoma (EHC) to identify its role in tumor progression.MethodsThe expression of Snail and Slug mRNA in 52 human tissue samples of EHC was investigated. The mRNA of Snail and Slug were quantified using reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. We then investigated transfection of Slug cDNA in endogenous E-cadherin-positive human EHC FRH0201 cells, selectively induced the loss of E-cadherin protein expression, and then small interfering RNA (siRNA) for inhibition of Slug expression in endogenous Slug-positive human EHC QBC939 cells, selectively induced the loss of Slug protein expression. A Boyden chamber transwell assay was used for invasion.ResultsSlug mRNA was overexpressed in 18 cases (34.6%) of EHC compared with adjacent noncancerous tissue. E-Cadherin protein expression determined in the same 52 cases by immunohistochemistry was significantly down-regulated in those cases with Slug mRNA overexpression (P = 0.0001). The tumor and nontumor ratio of Slug mRNA was correlated with nodal metastasis(p = 0.0102), distant metastasis (p = 0.0001)and Survival time(p = 0.0443). However, Snail mRNA correlated with neither E-cadherin expression nor tumor invasiveness. By inhibiting Slug expression by RNA interference, we found that reduced Slug levels upregulated E-cadherin and decreased invasion in QBC939 cell. When the QBC939 cells was infected with Slug cDNA,, significant E-cadherin was downregulated and increased invasion in QBC939 cell.ConclusionsThe results suggested that Slug expression plays an important role in both the regulation of E-cadherin expression and in the acquisition of invasive potential in human EHC. Slug is possibly a potential target for an antitumor therapy blocking the functions of invasion and metastasis in human EHCs.
Highlights
Cholangiocarcinoma is a cancer arising from bile duct epithelium
Three-year survival rates of 35 to 50% can be achieved in only a few numbers of patients when negative histological margins are attained at the time of surgery [1]. The reason for this poor prognosis is that cholangiocarcinoma exhibits extensive local invasion and frequent regional lymph node metastasis[2]. but the mechanisms through which Cholangiocarcinoma
Loss of heterozygosity of the E-cadherin gene, and CpG methylation around the promoter region of the E-cadherin gene were noted in human gastric cancer, breast cancer, and Hepatocarcinoma [7,8,9,10,11]
Summary
Cholangiocarcinoma is a cancer arising from bile duct epithelium. Three-year survival rates of 35 to 50% can be achieved in only a few numbers of patients when negative histological margins are attained at the time of surgery [1] The reason for this poor prognosis is that cholangiocarcinoma exhibits extensive local invasion and frequent regional lymph node metastasis[2]. The Slug transcription factor was reported to directly repress E-cadherin expression in many epithelial cancers associated with epithelial-mesenchymal transitions [12]. We can find no documentation regarding the expression of Snail or Slug in human EHC tissue. We investigated whether Slug represses E-cadherin expression in human EHC cells. Our evidence suggests that Slug, rather than Snail, may contribute to both E-cadherin expression and to the progression of EHCs
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