BACKGROUND & AIMS: Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. MATERIALS AND METHODS: We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480 colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. RESULTS: Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. CONCLUSIONS: Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
BACKGROUND & AIMS: Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. MATERIALS AND METHODS: We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. RESULTS:Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in humancolon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. CONCLUSIONS:Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
Authors: Sheng-Ru Shiou; Amar B Singh; Krishnan Moorthy; Pran K Datta; M Kay Washington; R Daniel Beauchamp; Punita Dhawan Journal: Cancer Res Date: 2007-02-15 Impact factor: 12.701
Authors: P D Leotlela; M S Wade; P H Duray; M J Rhode; H F Brown; D T Rosenthal; S K Dissanayake; R Earley; F E Indig; B J Nickoloff; D D Taub; O P Kallioniemi; P Meltzer; P J Morin; A T Weeraratna Journal: Oncogene Date: 2006-12-11 Impact factor: 9.867
Authors: Patricia Pintor Dos Reis; Rikki R Bharadwaj; Jerry Machado; Christina Macmillan; Melania Pintilie; Mahadeo A Sukhai; Bayardo Perez-Ordonez; Patrick Gullane; Jonathan Irish; Suzanne Kamel-Reid Journal: Cancer Date: 2008-12-01 Impact factor: 6.860
Authors: Simone Spaderna; Otto Schmalhofer; Mandy Wahlbuhl; Arno Dimmler; Katja Bauer; Aneesa Sultan; Falk Hlubek; Andreas Jung; Dennis Strand; Andreas Eger; Thomas Kirchner; Jürgen Behrens; Thomas Brabletz Journal: Cancer Res Date: 2008-01-15 Impact factor: 12.701
Authors: K Aigner; B Dampier; L Descovich; M Mikula; A Sultan; M Schreiber; W Mikulits; T Brabletz; D Strand; P Obrist; W Sommergruber; N Schweifer; A Wernitznig; H Beug; R Foisner; A Eger Journal: Oncogene Date: 2007-05-07 Impact factor: 9.867
Authors: Lenora W M Loo; Maarit Tiirikainen; Iona Cheng; Annette Lum-Jones; Ann Seifried; James M Church; Robert Gryfe; Daniel J Weisenberger; Noralane M Lindor; Steven Gallinger; Robert W Haile; David J Duggan; Stephen N Thibodeau; Graham Casey; Loïc Le Marchand Journal: Genes Chromosomes Cancer Date: 2013-01-23 Impact factor: 5.006
Authors: Naotake Funamizu; Chaoxin Hu; Curtis Lacy; Aaron Schetter; Geng Zhang; Peijun He; Jochen Gaedcke; Michael B Ghadimi; Thomas Ried; Harris G Yfantis; Dong H Lee; Jeffrey Subleski; Tim Chan; Jonathan M Weiss; Timothy C Back; Katsuhiko Yanaga; Nader Hanna; H Richard Alexander; Anirban Maitra; S Perwez Hussain Journal: Int J Cancer Date: 2013-02-15 Impact factor: 7.396
Authors: Zhe Liu; Yongjun Tian; Keigo Machida; Michael M C Lai; Guangxiang Luo; Steven K H Foung; Jing-hsiung James Ou Journal: J Biol Chem Date: 2012-10-24 Impact factor: 5.157
Authors: Christopher S Williams; Jessica K Bernard; Michelle Demory Beckler; Dana Almohazey; Mary Kay Washington; Jesse J Smith; Mark R Frey Journal: Carcinogenesis Date: 2015-04-27 Impact factor: 4.944