title: Multiple pathways regulate Cten in colorectal cancer without a Tensin switch.
abstract: CTEN/TNS4 is a member of the Tensin gene family. It localizes to focal adhesions and induces cell motility. The mechanisms regulating Cten expression are unclear although we have shown regulation by Kras in the colon and pancreas. In normal mammary cell lines, it is reportedly upregulated by epidermal growth factor receptor (EGFR) and STAT3 signalling and upregulation is accompanied by downregulation of Tensin 3 (Tensin switch). In this study, we investigated the roles of EGFR and STAT3 signalling in the regulation of Cten in colorectal cancer (CRC). In addition, we investigated calpain--a regulator of focal adhesion-associated proteins whose relevance to Cten has not been investigated. CRC cell lines were stimulated with epidermal growth factor (EGF). This resulted in an increase in Cten and Tensin 3 protein. Kras was knocked down and this resulted in downregulation of Cten and Tensin 3. We next investigated the role of STAT3 signalling. Activation and knockdown of STAT3 resulted in downregulation and upregulation, respectively, of Cten. Inhibition of calpain resulted in upregulation of both Cten and Tensin 3. As the regulators of Cten also seemed to regulate Tensin 3, we tested the interaction between Cten and Tensin 3. Cten was forcibly expressed or knocked down resulting, respectively, in upregulation and downregulation of Tensin 3. We conclude that in CRC, Cten is upregulated by EGFR and Kras but downregulated by STAT3. We show that calpain may be a negative regulator of Cten and that a Tensin switch does not occur and, if anything, Cten stabilizes Tensin 3.
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Hannah
authors: H
authors: Thorpe
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Maham
authors: M
authors: Akhlaq
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Darryl
authors: D
authors: Jackson
authors: King Abdullah International Medical Research Center, KSAU-HS, Riyadh, Saudi Arabia.
authors: Saleh
authors: S
authors: Al Ghamdi
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Sarah
authors: S
authors: Storr
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Stewart
authors: S
authors: Martin
authors: School of Medicine, University of Nottingham, Nottingham, UK.
authors: Mohammad
authors: M
authors: Ilyas
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000070876:Tensins; D014162:Transfection
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C117307:KRAS protein, human; D008840:Microfilament Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000603370:TNS3 protein, human; C000603371:TNS4 protein, human; D000070876:Tensins; C071482:calpeptin; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D002154:Calpain; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cten; EGF; Kras; STAT3; Tensin 3; calpain