CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis

Albasri, Abdulkader M.; Aleskandarany, Mohammed A.; Benhasouna, Ahmed; Powe, Desmond G.; Ellis, Ian O.; Ilyas, Mohammad; Green, Andrew

doi:10.1007/s10549-010-0890-3

Cited by 44 publications

(51 citation statements)

References 25 publications

(22 reference statements)

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“…These data would suggest that Cten can indeed enhance tumour metastasis, and would support our own data and other published data showing the association between high Cten expression and advanced disease stage in colorectal, breast, lung, thymic and gastric tumours (Sasaki et al, 2003a, b;Sakashita et al, 2008;Albasri et al, 2011).…”

Section: Cten Expression and Prognosissupporting

confidence: 91%

“…We have recently shown that high levels of Cten expression are associated with a poor prognosis in breast cancer (Albasri et al, 2011), and similar results have been reported in thymomas, gastric cancers and lung cancers (Sasaki et al, 2003a, b;Sakashita et al, 2008). The impact of Cten expression on clinical outcome may be related to its biological activity, which, in CRC cell lines at least, results in enhanced colony formation, resistance to staurosporineinduced apoptotic stress and increased cell motility (Albasri et al, 2009;Liao et al, 2009).…”

Section: Introductionsupporting

confidence: 62%

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

et al. 2011

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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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Section: Cten Expression and Prognosissupporting

confidence: 91%

Section: Introductionsupporting

confidence: 62%

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

et al. 2011

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“…We finally examined the relation between TNS4 mRNA expression levels and clinicopathological features in gastric cancer. A previous study reported that overexpression of TNS4 correlated with tumor size, histological grade, and axillary nodal involvement in invasive breast carcinoma (17). In colorectal cancer, high expression of TNS4 was reported to be associated with advanced Duke's stage and distant metastasis (18).…”

Section: Discussionmentioning

confidence: 97%

Clinical Significance of Tensin 4 Gene Expression in Patients with Gastric Cancer

Sawazaki

Oshima

Sakamaki

et al. 2017

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Gastric cancer is the fifth most common cancer in the world and the third leading cause of cancer-related death (1). The outcomes of gastric cancer have been improved by gastrectomy with D2 lymph-node dissection and advances in chemotherapy (2). The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that 1 year of adjuvant chemotherapy with S-1, an oral fluoropyrimidine, significantly improves outcomes in patients with stage II/III gastric cancer who undergo gastrectomy with D2 dissection (3). However, recurrence rates after curative resection and adjuvant chemotherapy remain high in gastric cancer. In the ACTS-GC study, the 5-year overall survival (OS) rate was 84.2% in those with stage II disease, 67.1% in those with stage IIIA disease, and 50.2% in those with stage IIIB disease, even after adjuvant chemotherapy with S-1 (4). Further improvements in outcomes are likely to require personalized therapy based on biomarker analysis.We have searched for biomarkers of gastric cancer using DNA microarray analysis in patients with stage II/III gastric cancer who underwent curative resection and received adjuvant chemotherapy with S-1. We found that expression of the human tensin 4 (TNS4) gene in gastric cancer tissue was 23.52-times higher than that in paired adjacent normal mucosa (unpublished data). We, thus, focused on the clinical significance of TNS4 gene expression in gastric cancer.TNS4 is a member of the tensin gene family (5) and is also known as COOH-terminus tensin-like molecule (CTEN) (6). This gene family comprises four members (TNS1, TNS2, TNS3, and TNS4) and their products are localized in the cytoplasmic tails of integrins at focal adhesions. Tensins play important roles in various biological processes, such as cell adhesion, migration, proliferation, differentiation, apoptosis, and invasion (6-9). TNS4 expression is up-regulated in many cancer types (10)(11)(12)(13)(14), suggesting that overexpression of TNS4 may play a critical role in tumorigenesis.In this study, we evaluated the clinical significance of the relative expression of TNS4 in patients with stage II/III gastric cancer who underwent curative resection followed by adjuvant chemotherapy with S-1.

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“…Despite some achievements, the prognosis is unsatisfactory and the mortality rate remains high. The onset and metastasis of tumors are closely associated with their external and internal microenvironments, which are subject to the structures, functions, and metabolism of the tissues involved (Albasri et al, 2009(Albasri et al, , 2011b. Independently originating from primitive mesenchymal tissues, gastrointestinal stromal tumors include smooth muscle cell-derived tumors, Schwann cell-derived tumors, and undifferentiated tumors that may have multiple differentiation capacities (Sakashita et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The enhanced mobility and invasion capability of tumor cells are largely responsible for initiating the progression and metastasis of tumors. Epithelial tumor cells lose their intrinsic characteristics and begin to resemble mesenchymal stem cells during EMT, thereby acquiring migration and invasion capabilities (Albasri et al, 2011b). Overexpression of CTEN in intestinal cancer cells can decrease the expression levels of EMT key molecules and epithelial marker E-cadherin protein, as well as induce EMT by promoting cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of susceptibility in intestinal stromal tumors

Yang

Chen²,

Zhang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We analyzed the susceptibility of intestinal stromal tumors using cell culture and proteomics. Human SGC7901 gastric cells were selected and divided into a blank control group (untransfected SGC7901 cells), a negative control group [SGC7901 cells transfected with negative interference control-small interfering RNA (siRNA)], and a COOHterminus tensin-like molecule (CTEN)-siRNA-1 group (SGC7901 cells transfected with CTEN-siRNA-1). The cells were successfully transfected and subjected to analyses of cell proliferation, cell cycle, cell invasion, CTEN expression, and proteomics. The percentages of cells in the G0/ G1, S, and G2/M phases were similar in the three groups (P > 0.05), and the OD values were also similar at 24, 48, and 72 h (P > 0.05). Compared with the levels in the blank and negative control groups, CTEN protein in the CTEN-siRNA-1 group decreased by 66 and 65%, respectively, and significantly fewer cells in the CTEN-siRNA-1 group were capable of invasion (P < 0.05). Proteomic analysis showed that in the CTEN-siRNA-1 group, 283 proteins were upregulated and 242 were downregulated; from these, the expression levels of E-cadherin and ERK proteins changed significantly. Silencing the expression of CTEN in intestinal stromal tumor cells reduces their invasion capability. Moreover, silencing CTEN at different stages can also regulate the expression levels of E-cadherin and ERK proteins.

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CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis

Cited by 44 publications

References 25 publications

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

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

Clinical Significance of Tensin 4 Gene Expression in Patients with Gastric Cancer

Proteomic analysis of susceptibility in intestinal stromal tumors

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