Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

American Association for Cancer Research (AACR) - Tập 68 Số 11 - Trang 4105-4115 - 2008
Cristina M. Karp1, Ting Ting Tan1, Robin Mathew2, Deidre Nelson1, Chandreyee Mukherjee1, Kurt Degenhardt1, Vassiliki Karantza‐Wadsworth2,3, Eileen White1,3
11Department of Molecular Biology and Biochemistry, Center for Advanced Biotechnology and Medicine, Rutgers University;
22Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey and
33The Cancer Institute of New Jersey, New Brunswick, New Jersey

Tóm tắt

Abstract Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]

Từ khóa


Tài liệu tham khảo

Degenhardt K, White E. A mouse model system to genetically dissect the molecular mechanisms regulating tumorigenesis. Clin Cancer Res 2006; 12: 5298–304.

Tan TT, Degenhardt K, Nelson DA, et al. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 2005; 7: 227–38.

Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21: 1621–35.

Degenhardt K, Chen G, Lindsten T, White E. BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2002; 2: 193–203.

Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Dev 2004; 18: 2095–107.

Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66: 8319–26.

Zavadil J, Bottinger EP. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764–74.

Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005; 17: 548–58.

Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 2003; 116: 1959–67.

Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.

Aigner K, Dampier B, Descovich L, et al. The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007; 26: 6979–88.

Bilder D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev 2004; 18: 1909–25.

Lu H, Bilder D. Endocytic control of epithelial polarity and proliferation in Drosophila. Nat Cell Biol 2005; 7: 1232–9.

Margolis B, Borg JP. Apicobasal polarity complexes. J Cell Sci 2005; 118: 5157–9.

Fogg VC, Liu CJ, Margolis B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J Cell Sci 2005; 118: 2859–69.

Perez D, White E. E1B 19K inhibits Fas-mediated apoptosis through FADD-dependent sequestration of FLICE. J Cell Biol 1998; 141: 1255–66.

Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 2003; 30: 256–68.

Albini A, Iwamoto Y, Kleinman HK, et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 1987; 47: 3239–45.

Chang YH, Chao Y, Hsieh SL, Lin WW. Mechanism of LIGHT/interferon-γ-induced cell death in HT-29 cells. J Cell Biochem 2004; 93: 1188–202.

Klampfer L, Huang J, Swaby LA, Augenlicht L. Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 2004; 279: 30358–68.

Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ, Tainsky MA. Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene 2003; 22: 4118–27.

Nusinzon I, Horvath CM. Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc Natl Acad Sci U S A 2003; 100: 14742–7.

Sakamoto S, Potla R, Larner AC. Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. J Biol Chem 2004; 279: 40362–7.

Simske JS, Koppen M, Sims P, Hodgkin J, Yonkof A, Hardin J. The cell junction protein VAB-9 regulates adhesion and epidermal morphology in C. elegans. Nat Cell Biol 2003; 5: 619–25.

Swisshelm K, Macek R, Kubbies M. Role of claudins in tumorigenesis. Adv Drug Deliv Rev 2005; 57: 919–28.

Ladwein M, Pape UF, Schmidt DS, et al. The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7. Exp Cell Res 2005; 309: 345–57.

Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4: 118–32.

Roh MH, Fan S, Liu CJ, Margolis B. The Crumbs3-PALS1 complex participates in the establishment of polarity in mammalian epithelial cells. J Cell Sci 2003; 116: 2895–906.

Klebes A, Knust E. A conserved motif in Crumbs is required for E-cadherin localisation and zonula adherens formation in Drosophila. Curr Biol 2000; 10: 76–85.

Lemmers C, Michel D, Lane-Guermonprez L, et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol Biol Cell 2004; 15: 1324–33.

Hurd TW, Gao L, Roh MH, Macara IG, Margolis B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol 2003; 5: 137–42.

Brabletz T, Jung A, Reu S, et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 2001; 98: 10356–61.

Murtagh J, McArdle E, Gilligan E, Thornton L, Furlong F, Martin F. Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. J Cell Biol 2004; 166: 133–43.

Giebel B, Wodarz A. Tumor suppressors: control of signaling by endocytosis. Curr Biol 2006; 16: R91–2.

Wodarz A, Hinz U, Engelbert M, Knust E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 1995; 82: 67–76.

Yang M, Nelson D, Funakoshi Y, Padgett RW. Genome-wide microarray analysis of TGFβ signaling in the Drosophila brain. BMC Dev Biol 2004; 4: 14.

Liu H, Radisky DC, Wang F, Bissell MJ. Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells. J Cell Biol 2004; 164: 603–12.

Guo W, Pylayeva Y, Pepe A, et al. β4 Integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006; 126: 489–502.

Aranda V, Haire T, Nolan ME, et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 2006; 8: 1235–45.

Martin TA, Jiang WG. Tight junctions and their role in cancer metastasis. Histol Histopathol 2001; 16: 1183–95.