Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3225-5) contains supplementary material, which is available to authorized users.

RETRACTED: Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP‐9

“…Our study showed that there was significantly more Six1 expression in TAMs in HCC tissues than in neighbouring non‐tumour tissues. Because of the close relationship, high Six1 expression and tumour metastasis and invasion, we hypothesized that the expression of Six1 in macrophages may contribute to promoting the invasive process in tumour cells. The human monocyte cell line THP‐1 is a well‐known model, suitable for studying the regulatory role of monocytes as well as macrophages .…”

SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial‐mesenchymal transition

“…SIX1 also regulates invasion in many cancers including colorectal cancer, cervical cancer, pancreatic cancer, and glioblastoma . From our clinicopathological data analysis, we found that SIX1 expression significantly associated with lymph node metastasis.…”

“…Similar to its important roles during growth, SIX1 also widely participates in regulating tumour initiation and progression. For example, SIX1 can regulate proliferation, invasion, epithelial‐mesenchymal transition (EMT), and apoptosis . Our study specifically investigated the function of SIX1 in regulating GC formation.…”

“…For example, SIX1 can regulate proliferation, invasion, epithelial-mesenchymal transition (EMT), and apoptosis. [20][21][22][23][24] Our study specifically investigated the function of SIX1 in regulating GC formation.…”

“…SIX1 also regulates invasion in many cancers including colorectal cancer, cervical cancer, pancreatic cancer, and glioblastoma. 20,[30][31][32] From our clinicopathological data analysis, we found that SIX1 expression significantly associated with lymph node metastasis. By performing Transwell assays, we found that upregulated SIX1 could obviously promote GC cell invasion, which could also be inhibited by SIX1 knockdown.…”