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

Abstract

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.

Overexpression of CTEN is associated with gefitinib resistance in non‑small cell lung cancer

“…Thorpe et al (13) demonstrated that CTEN may facilitate epithelial-mesenchymal transition (EMT) processes by preventing the degradation of Snail protein in colorectal cancer. Asiri et al (14) demonstrated that CTEN is a positive modulator of Src, and that CTEN may promote EMT and metastasis via post-transcriptional stabilization of Src protein in colorectal cancer. Notably, Hong et al (15) revealed that a proportion of nuclear-localized CTEN contributes toward cell proliferation in cancer cells.…”

A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

“…It was recently shown that the oncoprotein Src in endosomal membranes promoted exosome secretion and tumor progression [186]. Consistently, Src promotes EMT triggered by multiple EMT inducers including EGF [187], leptin [188], Cten [189], and δNp63γ [190]. Anti-EMT strategies involving targeting the TGFβ receptor or CDK2 may inhibit exosome/oncosome release from cancer cells [36].…”

The role of tensins in malignant neoplasms

“…Formation of these structures enables cells to migrate and contributes to invasion and metastasis of tumor cells [17]. Among tensins, tensin-4 is mainly reported as a molecule participating in EMT through various signaling pathways such as Ras/Raf/extracellular signal-regulated kinase (ERK), TGF-β, Akt/PI3K, and signal transducer and activator of transcription 3 (STAT3) and growth factors-related pathways [13,[18][19][20][21].…”