Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer

Abstract

CTEN/TNS4 is an oncogene in colorectal cancer (CRC), which can induce cell motility although its mechanistic basis of activity and the clinical implications of Cten expression are unknown. As Cten is in complex with integrins at focal adhesions, we hypothesised that it may interact with integrin-linked kinase (ILK). Through forced expression and knockdown of Cten in HCT116 and SW620 (respectively, showing low and high Cten expression), we showed that Cten could regulate ILK. However, inhibition of ILK after forced expression of Cten abrogated the motility-inducing effects of Cten, thereby demonstrating that the Cten-ILK interaction was functionally relevant. Combined knockdown of Cten and ILK had no additive effects on cell motility compared with knockdown of each individually. In order to investigate the clinical implications of Cten expression, a series of 462 CRCs were evaluated by immunohistochemistry. High expression of Cten was associated with advanced Dukes' stage (Po0.001), poor prognosis (Po0.001) and distant metastasis (P ¼ 0.008). The role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with a Cten expression vector into nude mice and (b) testing a series of primary human CRCs and their metastases by immunohistochemistry. Compared with controls, mice injected with cells expressing Cten developed larger tumours in the spleen (Po0.05) and liver (Po0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P ¼ 0.002). We conclude that Cten expression is of prognostic significance in CRC, and we delineate a Cten-ILK pathway controlling cell motility and possibly promoting metastasis. Oncogene (2011Oncogene ( ) 30, 2997 doi:10.1038/onc.2011 published online 21 February 2011 Keywords: Cten; integrin-linked kinase; metastasis Introduction C-terminal tensin-like (Cten, TNS4) is a member of the Tensin gene family. This gene family comprises four members (TNS1, TNS2, TNS3 and TNS4/Cten) and their products are localised to the cytoplasmic tails of integrins at focal adhesions. Tensins have an important role in various biological processes such as cell adhesion, migration, proliferation, differentiation, apoptosis and invasion (Lo et al., 1994;Chen et al., 2000;Lo, 2004). Human TNS1, TNS2 and TNS3 are highly homologous at their N-and C-termini, but TNS4/ COOH-terminus tensin-like molecule (Cten) is a smaller protein, which shows C-terminus homology but does not contain the N-terminus actin-binding domain that is present in the other tensin proteins (Lo and Lo, 2002). Tensin family proteins interact with several structural and signalling molecules such as vinculin, paxillin, Src, focal adhesion kinase, phosphatidylinositol-3-kinase and Crk-associated substrate p130 CAS , actin as well as integrins. As Cten is a recently described gene, data about its downstream targets are sparse, although recent studies suggest that Cten signalling occurs through the Stat3 pathway (Barbie...

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