Abstract
BackgroundEpithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Assessment of transcription factors involved in these two mechanisms can help to identify new targets for an oncological therapy. In this study, we focused on the evaluation of the transcription factor Six1 (Sine oculis 1). This protein is involved in embryologic development and its contribution to carcinogenesis has been described in several studies.MethodsImmunohistochemistry against Six1 was performed on a tissue microarray containing specimens of primary pancreatic ductal adenocarcinomas (PDAC) of 139 patients. Nuclear and cytoplasmic expression was evaluated and correlated to histopathological parameters. Expression of Six1 was inhibited transiently by siRNA in Panc1 and BxPc3 cells and stably by shRNA in Panc1 cells. Expression analysis of CDH1 and Vimentin mRNA was performed and cell motility was tested in a migration assay. Panc1 cells transfected with Six1 shRNA or scrambled shRNA were injected subcutaneously into nude mice. Tumour growth was observed for four weeks. Afterwards, tumours were stained against Six1, CD24 and CD44.ResultsSix1 was overexpressed in the cytoplasm and cellular nuclei in malignant tissues (p < 0.0001). No correlation to histopathological parameters could be detected. Six1 down-regulation decreased pancreatic cancer cell motility in vitro. CDH1 and vimentin expression was decreased after inhibition of the expression of Six1. Pancreatic tumours with impaired expression of Six1 showed significantly delayed growth and displayed loss of the CD24+/CD44+ phenotype.ConclusionWe show that Six1 is overexpressed in human PDAC and that its inhibition results in a decreased tumour progression in vitro and in vivo. Therefore, targeting Six1 might be a novel therapeutic approach in patients with pancreatic cancer.
Highlights
Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis
Expression of Six1 in pancreatic ductal adenocarcinoma and its histopathological correlation Patient characteristics and clinical specimens Tissue samples from 139 patients suffering from primary pancreatic cancer were evaluated by IHC, out of these, sufficient material and data for final analysis were available in 137 cases
We show that inhibition of Six1 leads to decreased cell motility in Panc1 and BxPc3 cells
Summary
Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Pancreatic cancer spreads rapidly and is highly resistant to chemotherapy These features are determined by several biological features, which are considered to be hallmarks of tumour development and dissemination [2]. EMT is strongly connected to the concept of cancer stem cells (CSC) [4] In this model, CSC represent only a minor fraction of a tumour but are hypothesized to be crucially involved in its progression [5]. CSC represent only a minor fraction of a tumour but are hypothesized to be crucially involved in its progression [5] They can divide infinitely and are strongly resistant to chemotherapeutics. In good accordance with this assumption, Martin et al showed that EMT augments self-renewal capability [6]
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