title: 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 (P<0.001), poor prognosis (P<0.001) and distant metastasis (P=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 (P<0.05) and liver (P<0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P=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.
authors.affiliation: Division of Pathology, Nottingham University, Nottingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Albasri
authors.forename: S
authors.initials: S
authors.lastname: Al-Ghamdi
authors.forename: W
authors.initials: W
authors.lastname: Fadhil
authors.forename: M
authors.initials: M
authors.lastname: Aleskandarany
authors.forename: Y-C
authors.initials: YC
authors.lastname: Liao
authors.forename: D
authors.initials: D
authors.lastname: Jackson
authors.forename: D N
authors.initials: DN
authors.lastname: Lobo
authors.forename: S H
authors.initials: SH
authors.lastname: Lo
authors.forename: R
authors.initials: R
authors.lastname: Kumari
authors.forename: L
authors.initials: L
authors.lastname: Durrant
authors.forename: S
authors.initials: S
authors.lastname: Watson
authors.forename: K B
authors.initials: KB
authors.lastname: Kindle
authors.forename: M
authors.initials: M
authors.lastname: Ilyas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000070876:Tensins; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099200:Scaffold Protein ILK
chemical_list: D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000070876:Tensins; D000099200:Scaffold Protein ILK; C000603371:TNS4 protein, human; C000603393:Tns4 protein, mouse