Cten Is Targeted by Kras Signalling to Regulate Cell Motility in the Colon and Pancreas

Abstract

CTEN/TNS4 is an oncogene in colorectal cancer (CRC) which enhances cell motility although the mechanism of Cten regulation is unknown. We found an association between high Cten expression and KRAS/BRAF mutation in a series of CRC cell lines (p = 0.03) and hypothesised that Kras may regulate Cten. To test this, Kras was knocked-down (using small interfering (si)RNA) in CRC cell lines SW620 and DLD1 (high Cten expressors and mutant for KRAS). In each cell line, Kras knockdown was mirrored by down-regulation of Cten Since Kras signals through Braf, we tested the effect of Kras knockdown in CRC cell line Colo205 (which shows high Cten expression and is mutant for BRAF but wild type for KRAS). Cten levels were unaffected by Kras knockdown whilst Braf knockdown resulted in reduced Cten expression suggesting that Kras signals via Braf to regulate Cten. Quantification of Cten mRNA and protein analysis following proteasome inhibition suggested that regulation was of Cten transcription. Kras knockdown inhibited cell motility. To test whether this could be mediated through Cten, SW620 cells were co-transfected with Kras specific siRNAs and a Cten expression vector. Restoring Cten expression was able to restore cell motility despite Kras knockdown (transwell migration and wounding assay, p<0.001 for both). Since KRAS is mutated in many cancers, we investigated whether this relationship could be demonstrated in other tumour models. The experiments were repeated in the pancreatic cancer cell lines Colo357 & PSN-1(both high Cten expressors and mutant for KRAS). In both cell lines, Kras was shown to regulate Cten and forced expression of Cten was able to rescue loss of cell motility following Kras knockdown in PSN-1 (transwell migration assay, p<0.001). We conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility.

ERK-ERF-EGR1, a novel switch underlying acquisition of a motile phenotype

“…30 Cten is upregulated and associates with a poor prognosis in breast cancer, thymomas, gastric cancers and lung cancers, and according to a recent report mutant RAS upregulates cten expression. 31 Because tensin family proteins interact with several components of focal adhesion sites (e.g., vinculin and paxillin) they are thought to stabilize cell-to-matrix associations. Importantly, stimulation of mammary cells with EGF is followed by a transcriptional upregulation of cten, concomitant with downregulation of tensin 3.…”

From tissue invasion to glucose metabolism: the many aspects of signal transducer and activator of transcription 3 pro-oncogenic activities

“…Interestingly, dissection of the latter indicates that in the C and WT tumour-derived cell lines the aggressive phenotype could correlate with disrupted distribution of adherent and tight junctions, loss of cortical actin and development of actin stress fibres, mediated for a good part by the newly identified STAT3 target Cten (13). Cten is known to mediate EGFinduced migration (12), to promote cell motility of colon and pancreas cancer cells, and to be overexpressed in late stage epithelial tumours of different kind, often correlating with STAT3 constitutive activity (14). CTEN expression is particularly elevated in the highly aggressive and invasive inflammatory breast cancers, together with high EGFR and HER2 levels, loss of oestrogen receptor and lymph node metastasis (12).…”

C-terminal tensin-like (CTEN): A promising biomarker and target for cancer

“…Despite of its low expression in the normal kidney, cten is further downregulated in kidney cancers (Martuszewska et al, 2009). Although it may not be expressed in other normal tissues, cten expression has been found to increase significantly in many types of cancer including thymoma, gastric, colorectal, breast, lung, skin, and pancreatic cancer (Liao et al, 2009, Sasaki et al, 2003b, Sasaki et al, 2003a, Katz et al, 2007, Albasri et al, 2011b, Albasri et al, 2011c, Al-Ghamdi et al, 2011, Sjoestroem et al, 2013, Li et al, 2010, Al-Ghamdi et al, 2013, Sakashita et al, 2008), suggesting that overexpression of cten in certain tissues may play a critical role in tumorigenesis.…”

“…Cten expression is up-regulated by EGF, FGF2 (fibroblast growth factor 2), TGF-β (transforming growth factor beta), NGF (nerve growth factor), PDGF (platelet-derived growth factor), IGF-1 (insulin-like growth factor 1), IL-6 (interleukin 6) and IL-13 (interleukin 13) (Hung et al, 2013) mainly through the RAS-Raf-Mek, PI3K-Akt and Stat3 pathways activated by these cancer associated growth factors and cytokines (Hung et al, 2013, Barbieri et al, 2010, Al-Ghamdi et al, 2011). This may partially explain how cten levels increase dramatically in various cancers.…”