Rac1b negatively regulates TGF-β1-induced cell motility in pancreatic ductal epithelial cells by suppressing Smad signalling

Oncotarget

Volumn 5, Issue 1, 2014, Pages 277-290

  Ungefroren, Hendrik ^a,b   Sebens, Susanne ^b   Giehl, Klaudia ^c   Helm, Ole ^b   Groth, Stephanie ^a,b   Fändrich, Fred ^b   Röcken, Christoph ^b   Sipos, Bence ^d   Lehnert, Hendrik ^a   Gieseler, Frank ^a  

^a UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^b UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^c JUSTUS LIEBIG UNIVERSITY   (Germany)

^d UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

Author keywords

Cell migration; Pancreatic ductal adenocarcinoma; Rac1; Rac1b; Smad; TGF 1

Indexed keywords

PROTEIN RAC1B; RAC1 PROTEIN; RNA; SMAD PROTEIN; SMAD2 PROTEIN; SMAD3 PROTEIN; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR SLUG; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; GUANOSINE TRIPHOSPHATE; RAC1 PROTEIN, HUMAN; SMAD2 PROTEIN, HUMAN; SMAD3 PROTEIN, HUMAN;

ARTICLE; CANCER CELL CULTURE; CARBOXY TERMINAL SEQUENCE; CELL MIGRATION; CELL MIGRATION ASSAY; CELL MOTILITY; CELL STRAIN COLO357; CELL STRAIN H6C7; CELL STRAIN PANC 1; CHRONIC PANCREATITIS; CLINICAL ARTICLE; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; EPITHELIUM CELL; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; PANCREAS; PANCREAS ADENOCARCINOMA; PANCREAS DUCT; PANCREATIC DUCTAL EPITHELIAL CELL; PROMOTER REGION; PROTEIN DEPHOSPHORYLATION; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REGULATORY MECHANISM; REPORTER GENE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ISOLATION; SIGNAL TRANSDUCTION; SLUG GENE; CELL MOTION; CYTOLOGY; EPITHELIAL MESENCHYMAL TRANSITION; GENETIC TRANSFECTION; GENETICS; METABOLISM; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; PHOSPHORYLATION; PHYSIOLOGY; TUMOR CELL LINE;

CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; CELL MOVEMENT; EPITHELIAL CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; GUANOSINE TRIPHOSPHATE; HUMANS; PANCREATIC DUCTS; PANCREATIC NEOPLASMS; PHOSPHORYLATION; RAC1 GTP-BINDING PROTEIN; SIGNAL TRANSDUCTION; SMAD2 PROTEIN; SMAD3 PROTEIN; TRANSFECTION; TRANSFORMING GROWTH FACTOR BETA1;

EID: 84893876660     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.1696     Document Type: Article

References (43)

1. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg. Oncol. 2002; 10: 153-169.
2. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006; 20: 1218-1249.
3. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321: 1801-1806.
4. Miyazono K, Suzuki H, Imamura T. Regulation of TGF-beta signaling and its roles in progression of tumors. Cancer Sci. 2003; 94: 230-234.
5. Inman GJ. Switching TGFβ from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev. 2011; 21: 93-99.
6. Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006; 20: 3130-3146.
7. Ijichi H, Chytil A, Gorska AE, Aakre ME, Fujitani Y, Fujitani S, Wright CV, Moses HL. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev. 2006; 20: 3147-3160.
8. Heid I, Lubeseder-Martellato C, Sipos B, Mazur PK, Lesina M, Schmid RM, Siveke JT. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology. 2011; 141: 719-730.
9. Parri M, Chiarugi P. Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal. 2010; 8: 23.
10. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008; 9: 690-701.
11. Mack NA, Whalley HJ, Castillo-Lluva S, Malliri A. The diverse roles of Rac signaling in tumorigenesis. Cell Cycle. 2011; 10: 1571-1581.
12. Jordan P, Brazao R, Boavida MG, Gespach C, Chastre E. Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene. 1999; 18: 6835-6839.
13. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene. 2000; 19: 3013-3020.
14. Haeusler LC, Hemsath L, Fiegen D, Blumenstein L, Herbrand U, Stege P, Dvorsky R, Ahmadian MR. Purification and biochemical properties of Rac1, 2, 3 and the splice variant Rac1b. Methods Enzymol. 2006; 406: 1-11.
15. Fiegen D, Haeusler LC, Blumenstein L, Herbrand U, Dvorsky R, Vetter IR, Ahmadian MR. Alternative splicing of Rac1 generates Rac1b, a self-activating GTPase. J Biol Chem. 2004; 279: 4743-4749.
16. Matos P, Jordan P. Expression of Rac1b stimulates NF-kappaB-mediated cell survival and G1/S progression. Exp Cell Res. 2005; 305: 292-299.
17. Matos P, Jordan P. Increased Rac1b expression sustains colorectal tumor cell survival. Mol Cancer Res. 2008; 6: 1178-1184.
18. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005; 436: 123-127.
19. Orlichenko L, Geyer R, Yanagisawa M, Khauv D, Radisky ES, Anastasiadis PZ, Radisky DC. The 19-amino acid insertion in the tumor-associated splice isoform Rac1b confers specific binding to p120 catenin. J Biol Chem. 2010; 285: 19153-19161.
20. Matos P, Collard JG, Jordan P. Tumor-related alternatively spliced Rac1b is not regulated by Rho-GDP dissociation inhibitors and exhibits selective downstream signaling. J Biol Chem. 2003; 278: 50442-50448.
21. Ungefroren H, Groth S, Sebens S, Lehnert H, Gieseler F, Fändrich F. Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer. 2011; 10: 67.
22. Geismann C, Morscheck M, Koch D, Bergmann F, Ungefroren H, Arlt A, Tsao M, Bachem MG, Altevogt P, Sipos B, Fölsch UR, Schäfer H, Sebens Müerköster S. Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer. Cancer Res. 2009; 69: 4517-4526.
23. Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, O'Young G, Quon D, Henson M, Damm DL, Muiru GT, Murphy A, Higgins LS, Chakravarty S, Wong DH. Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol. 2007; 72: 152-161.
24. Medicherla S, Li L, Ma JY, Kapoun AM, Gaspar NJ, Liu YW, Mangadu R, O'Young G, Protter AA, Schreiner GF, Wong DH, Higgins LS. Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment. Anticancer Res. 2007; 27: 4149-4157.
25. Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008; 7: 829-840.
26. Levy L, Hill CS. Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol. 2005; 25: 8108-8125.
27. Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M, Imamura J, Tanaka Y, Tateishi K, Ikenoue T, Kawakami T, Arakawa Y, Miyagishi M, Taira K, Kawabe T, Omata M. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene. 2005; 24: 662-671.
28. Saito D, Kyakumoto S, Chosa N, Ibi M, Takahashi N, Okubo N, Sawada S, Ishisaki A, Kamo M. Transforming growth factor-β1 induces epithelial-mesenchymal transition and integrin a3β1-mediated cell migration of HSC-4 human squamous cell carcinoma cells through Slug. J Biochem. 2013; 153, 303-315.
29. Schniewind B, Groth S, Sebens Müerköster S, Sipos B, Schäfer H, Kalthoff H, Fändrich F, Ungefroren H. Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function. Oncogene. 2007; 26: 4850-4862.
30. Brandl M, Seidler B, Haller F, Adamski J, Schmid RM, Saur D, Schneider G. IKK(a) controls canonical TGF(β)-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells. J Cell Sci. 2010; 123: 4231-4239.
31. Nimnual AS, Taylor LJ, Nyako M, Jeng HH, Bar-Sagi D. Perturbation of cytoskeleton dynamics by the opposing effects of Rac1 and Rac1b. Small Gtpases. 2010; 1: 89-97.
32. Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem. 2004; 279: 24505-24513.
33. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 2002; 115: 3193-3206.
34. Zhou C, Licciulli S, Avila JL, Cho M, Troutman S, Jiang P, Kossenkov AV, Showe LC, Liu Q, Vachani A, Albelda SM, Kissil JL. The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis. Oncogene. 2013; 32: 903-909.
35. Matos P, Kotelevets L, Goncalves V, Henriques A, Zerbib P, Moyer MP, Chastre E, Jordan P. Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b. Neoplasia. 2013; 15: 102-111.
36. Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG, Gold LI, Korc M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993; 105: 1846-1856.
37. Grippo PJ, Tuveson DA. Deploying mouse models of pancreatic cancer for chemoprevention studies. Cancer Prev Res (Phila). 2010; 3: 1382-1387.
38. Jinnin M, Ihn H, Tamaki K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-β1-induced extracellular matrix expression. Mol Pharmacol. 2006; 69: 597-607.
39. Chen WB, Lenschow W, Tiede K, Fischer JW, Kalthoff H, Ungefroren H. Smad4/DPC4-dependent regulation of biglycan gene expression by transforming growth factor-beta in pancreatic tumor cells. J Biol Chem. 2002; 277: 36118-36128.
40. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB Danenberg KL, Tempero MA, Spellman PT, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011; 17: 500-503.
41. Stähle M, Veit C, Bachfischer U, Schierling K, Skripczynski B, Hall A, Gierschik P, Giehl K. Mechanisms in LPA-induced tumor cell migration: critical role of phosphorylated ERK. J Cell Sci. 2003; 116: 3835-3846.
42. Mandel K, Seidl D, Rades D, Lehnert H, Gieseler F, Hass R, Ungefroren H. Characterization of spontaneous and TGF-β-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology. PLoS One. 2013; 8: e56591.
43. Limame R, Wouters A, Pauwels B, Fransen E, Peeters M, Lardon F, De Wever O, Pauwels P. Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PLoS One. 2012: 7: e46536.