Multiple pathways regulate Cten in colorectal cancer without a Tensin switch

Molecular Carcinogenesis

Akhlaq

et al. 2017

Self Cite

Cten promotes cell migration however the knowledge of underlying signalling pathways is sparse. We have shown that Cten downregulates E-cadherin, a feature of epithelial to mesenchymal transition (EMT). This prompted us to investigate whether Cten further contributed to EMT processes to regulate cell motility. The regulation of Snail by Cten was investigated following overexpression, knockdown (by RNA-interference) or knockout of Cten in HCT116, Caco-2 and SW620 colorectal cancer (CRC) cell lines. Subsequently, the cycloheximide (CHX) pulse chase assay was used to investigate changes in Snail protein stability and the functional relevance of Cten-Snail signalling was investigated. Snail was identified as a downstream target of Cten signalling using multiple approaches of Cten expression manipulation. Furthermore, this activity was mediated through the SH2 domain of Cten. The CHX assay confirmed that Cten was regulating Snail at a post transcriptional level and this was through the prevention of Snail degradation. Cell migration, invasion and colony formation efficiency were increased following forced expression of GFP-Cten but subsequently lost when Snail was knocked down, demonstrating a functional Cten-Snail signalling axis. In conclusion, we have described a novel Cten-Snail signaling pathway that contributes to cell motility in CRC, mediated by the stabilization of Snail protein. This finding potentially furthers the understanding of EMT regulatory networks in cancer metastasis.

Section: Introductionmentioning

confidence: 63%

Cten promotes epithelial‐mesenchymal transition through the post‐transcriptional stabilization of Snail

Thorpe

Molecular Carcinogenesis

Akhlaq

et al. 2017

Self Cite

“…showing the role of Her2 in upregulating Cten in breast cancer cell lines. Furthermore, we and others have also found that Cten could be under the regulation of several cytokines such as IL6/Stat3 and growth factors, including EGF, NGF and FGF2 which also induces cell motility . The present study directly shows for the first time an essential role for Cten in TGF‐β1‐induced EMT and cell motility in CRC cells and that this may be through upregulation of the Src/ROCK1/Snail signalling pathway.…”

Section: Discussionmentioning

confidence: 70%

“…Further reports suggested that Cten is regulated by KRAS in both CRC and pancreatic cancer cells . Cten expression was also shown to be negatively regulated by STAT3 in CRC cell lines, whereas others have found that Cten is upregulated by STAT3 in human lung cancer cells . How Cten is activated and regulated in these tumours is unclear; nonetheless, multiple pathways seem to be involved, and it appears to be largely dependent on tissue type or context.…”

Section: Introductionmentioning

confidence: 99%

TGFβ1‐induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer

Int J Experimental Path

Raposo

Alfahed

et al. 2018

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Summary Cten (C‐terminal tensin‐like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial‐mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF‐β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF‐β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF‐β1 signalling was modulated by either stimulation with TGF‐β1 or knockdown of TGF‐β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF‐β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620ΔCten). When TGF‐β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers (Snail, Rock, N‐cadherin, Src). Cell migration and cell invasion were significantly increased following TGF‐β1 stimulation and lost by TGF‐β1 knockdown. TGF‐β1 stimulation of the SW620ΔCten cell line resulted in selective loss of the effect of TGF‐β1 signalling pathway on EMT and cell motility while the stimulatory effect on cell proliferation was retained. These data suggested Cten may play an essential role in mediating TGF‐β1‐induced EMT and cell motility and may therefore play a role in metastasis in CRC.

“…Additionally, previous studies have suggested that Src protein stabilization is most likely to be induced through the up‐regulation of Akt/mTOR/4E‐BP1 pathways and inhibition of calpain‐mediated Src protein degradation by ErbB2 signaling . Cten has been shown to be induced by ErbB2 signaling and negatively regulated by calpain . One can conjecture that the ErbB2 pathway could protect Cten through calpain inhibition and this in turn could lead to Src protein stabilization.…”

Section: Discussionmentioning

confidence: 98%

“…Tensins localise to focal adhesions and absence of the capability to bind actin filaments is thought to be essential to the role of Cten . The importance of Cten is underscored by data showing that it is a common and functionally active target for a multitude of different signaling pathways …”

Section: Introductionmentioning

confidence: 99%

Cten promotes Epithelial–Mesenchymal Transition (EMT) in colorectal cancer through stabilisation of Src

Pathology International

Toss

Raposo

et al. 2019

Self Cite

Cten is an oncogene promoting EMT in many signaling pathways, namely through Snail. We investigated whether Cten function could be mediated through Src. Cten levels were modulated by forced expression in HCT116 and gene knockdown in SW620 CRC (colorectal cancer) cell lines. In all cell lines, Cten was a positive regulator of Src expression. The functional importance of Src was tested by simultaneous Cten overexpression and Src knockdown. This resulted in abrogation of Cten motility‐inducing activity and reduction of colony formation ability together with failure to induce Cten targets. In SW620ΔCten reduced Src expression increased following restoration of Cten, also leading to increased cell motility and colony formation, which were lost if Src was concomitantly knocked down. By qRT‐PCR we showed modulation of Cten had no effect on Src mRNA. However, a CHX pulse chase assay demonstrated stabilization of Src protein by Cten. Finally, expression of Cten and Src was tested in a series of 84 primary CRCs and there was a significant correlation between them (P = 0.001). We conclude that Src is a novel and functionally important target of the Cten signaling pathway and that Cten protein causes post‐transcriptional stabilization of Src in promoting EMT and possibly metastasis in CRC.