Abstract
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.
Highlights
Colorectal cancer (CRC) is a major global health problem, with 1.36 million new cases being reported in 2012, and over 600,000 deaths due to the disease occurring the same year [1]
In order to ascertain the potential effect of HH signalling on Wnt signalling output, the HH pathway was inhibited in the SW480 cell line by treatment with cyclopamine, compared with vehicle control
It has been estimated that around 90% of all cancer deaths are caused by metastasis, and around half of all patients presenting with CRC have advanced disease when presenting at the clinic [32,33]
Summary
Colorectal cancer (CRC) is a major global health problem, with 1.36 million new cases being reported in 2012, and over 600,000 deaths due to the disease occurring the same year [1]. Other work on gastric adenocarcinoma cell lines showed HH to induce the Wnt inhibitor sFRP-1, but as this acts upstream of the APC-mediated β-catenin destruction complex (disrupted in the vast majority of CRCs) is unlikely to be of consequence in colorectal tumours [14]. Counter to these reports, SMO knockdown in CRC cell lines has been shown to suppress β-catenin-dependent transcription [9]. To this end we measured the response of catenin-related transcription (using the TOPFLASH Tcf-reporter assay [16]) to cyclopamine with or without the addition of exogenous amino terminal SHH peptide
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