The Wnt/β-catenin/T-cell Factor 4 Pathway Up-regulates High-mobility Group A1 Expression in Colon Cancer

Overview

Journal Cell Biochem Funct

Specialties Biochemistry
Cell Biology

Date 2012 Sep 11

PMID 22961697

Citations 28

Authors

Bethany M Bush

Ashton T Brock

Jiayue A Deng

Ronald A Nelson

Takita Felder Sumter

Affiliations

Soon will be listed here.

Abstract

High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the β-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the β-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the β-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β-catenin/TCF-4 signalling.

Citing Articles

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HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression.

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References

Dolde C, Mukherjee M, Cho C, Resar L . HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat. 2002; 71(3):181-91. DOI: 10.1023/a:1014444114804. View

Schwartz D, Wu R, Kardia S, Levin A, Huang C, Shedden K . Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas. Cancer Res. 2003; 63(11):2913-22. View

Evans A, Lennard T, Davies B . High-mobility group protein 1(Y): metastasis-associated or metastasis-inducing?. J Surg Oncol. 2004; 88(2):86-99. DOI: 10.1002/jso.20136. View

Fedele M, Fusco A . HMGA and cancer. Biochim Biophys Acta. 2010; 1799(1-2):48-54. DOI: 10.1016/j.bbagrm.2009.11.007. View

Hanahan D, Weinberg R . The hallmarks of cancer. Cell. 2000; 100(1):57-70. DOI: 10.1016/s0092-8674(00)81683-9. View

Grade M, Hummon A, Camps J, Emons G, Spitzner M, Gaedcke J . A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets. Int J Cancer. 2010; 128(5):1069-79. PMC: 3008507. DOI: 10.1002/ijc.25453. View

Wood L, MAHER J, Bunton T, Resar L . The oncogenic properties of the HMG-I gene family. Cancer Res. 2000; 60(15):4256-61. View

He T, Sparks A, Rago C, Hermeking H, Zawel L, DA COSTA L . Identification of c-MYC as a target of the APC pathway. Science. 1998; 281(5382):1509-12. DOI: 10.1126/science.281.5382.1509. View

Bodmer W, Cottrell S, Frischauf A, Kerr I, Murday V, Rowan A . Genetic analysis of colorectal cancer. Princess Takamatsu Symp. 1989; 20:49-59. View

10.

Flohr A, Rogalla P, Bonk U, Puettmann B, Buerger H, Gohla G . High mobility group protein HMGA1 expression in breast cancer reveals a positive correlation with tumour grade. Histol Histopathol. 2003; 18(4):999-1004. DOI: 10.14670/HH-18.999. View

11.

Zeilstra J, Joosten S, Dokter M, Verwiel E, Spaargaren M, Pals S . Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008; 68(10):3655-61. DOI: 10.1158/0008-5472.CAN-07-2940. View

12.

Pierantoni G, Agosti V, Fedele M, Bond H, Caliendo I, Chiappetta G . High-mobility group A1 proteins are overexpressed in human leukaemias. Biochem J. 2003; 372(Pt 1):145-50. PMC: 1223365. DOI: 10.1042/BJ20021493. View

13.

Kim D, Park Y, Park C, Son K, Nam E, Shin H . Expression of the HMGI(Y) gene in human colorectal cancer. Int J Cancer. 1999; 84(4):376-80. DOI: 10.1002/(sici)1097-0215(19990820)84:4<376::aid-ijc8>3.0.co;2-n. View

14.

Yan S, Zhou C, Zhang W, Zhang G, Zhao X, Yang S . beta-Catenin/TCF pathway upregulates STAT3 expression in human esophageal squamous cell carcinoma. Cancer Lett. 2008; 271(1):85-97. DOI: 10.1016/j.canlet.2008.05.035. View

15.

Berlingieri M, Pierantoni G, Giancotti V, Santoro M, Fusco A . Thyroid cell transformation requires the expression of the HMGA1 proteins. Oncogene. 2002; 21(19):2971-80. DOI: 10.1038/sj.onc.1205368. View

16.

Cleynen I, Van de Ven W . The HMGA proteins: a myriad of functions (Review). Int J Oncol. 2008; 32(2):289-305. View

17.

Fedele M, Bandiera A, Chiappetta G, Battista S, Viglietto G, Manfioletti G . Human colorectal carcinomas express high levels of high mobility group HMGI(Y) proteins. Cancer Res. 1996; 56(8):1896-901. View

18.

Rowan A, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A . APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits". Proc Natl Acad Sci U S A. 2000; 97(7):3352-7. PMC: 16243. DOI: 10.1073/pnas.97.7.3352. View

19.

MUNEMITSU S, Albert I, Souza B, Rubinfeld B, Polakis P . Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 1995; 92(7):3046-50. PMC: 42356. DOI: 10.1073/pnas.92.7.3046. View

20.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View