Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer

Authors: Chien-Hsing Lee, Hsing-Wen Hung, Pei-Hsin Hung, Yi-Shing Shieh

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.

Results

We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer.

Conclusions

EGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A: Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem. 1998, 273: 10823-10826. 10.1074/jbc.273.18.10823CrossRefPubMed
3.
Jankowski JA, Bruton R, Shepherd N, Sanders DS: Cadherin and catenin biology represent a global mechanism for epithelial cancer progression. Mol Pathol. 1997, 50: 289-290. 10.1136/mp.50.6.289PubMedCentralCrossRefPubMed
4.
Barker N, Morin PJ, Clevers H: The Yin-Yang of TCF/beta-catenin signaling. Adv Cancer Res. 2000, 77: 1-24. full_textCrossRefPubMed
5.
Mareel MM, Behrens J, Birchmeier W, De Bruyne GK, Vleminckx K, Hoogewijs A, Fiers WC, Van Roy FM: Down-regulation of E-cadherin expression in Madin Darby canine kidney (MDCK) cells inside tumors of nude mice. Int J Cancer. 1991, 47: 922-928. 10.1002/ijc.2910470623CrossRefPubMed
6.
Clevers H, Wetering van de M: TCF/LEF factors earn their wings. Trends Genet. 1997, 13: 485-489. 10.1016/S0168-9525(97)01305-XCrossRefPubMed
7.
Aoki M, Hecht A, Kruse U, Kemler R, Vogt PK: Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. Proc Natl Acad Sci USA. 1999, 96: 139-144. 10.1073/pnas.96.1.139PubMedCentralCrossRefPubMed
8.
Odajima T, Sasaki Y, Tanaka N, Kato-Mori Y, Asanuma H, Ikeda T, Satoh M, Hiratsuka H, Tokino T, Sawada N: Abnormal beta-catenin expression in oral cancer with no gene mutation: correlation with expression of cyclin D1 and epidermal growth factor receptor, Ki-67 labeling index, and clinicopathological features. Hum Pathol. 2005, 36: 234-241. 10.1016/j.humpath.2004.12.009CrossRefPubMed
9.
Shieh YS, Chang LC, Chiu KC, Wu CW, Lee HS: Cadherin and catenin expression in mucoepidermoid carcinoma: correlation with histopathologic grade, clinical stage, and patient outcome. J Oral Pathol Med. 2003, 32: 297-304.CrossRefPubMed
10.
Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y: Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998, 58: 2524-2527.PubMed
11.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science. 1998, 281: 1509-1512. 10.1126/science.281.5382.1509CrossRefPubMed
12.
Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y, Miyoshi Y: Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res. 1998, 58: 1021-1026.PubMed
13.
Miyoshi Y, Iwao K, Nawa G, Yoshikawa H, Ochi T, Nakamura Y: Frequent mutations in the beta-catenin gene in desmoid tumors from patients without familial adenomatous polyposis. Oncol Res. 1998, 10: 591-594.PubMed
14.
Chan EF, Gat U, McNiff JM, Fuchs E: A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999, 21: 410-413. 10.1038/7747CrossRefPubMed
15.
Garcia-Rostan G, Tallini G, Herrero A, D'Aquila TG, Carcangiu ML, Rimm DL: Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 1999, 59: 1811-1815.PubMed
16.
Ashihara K, Saito T, Mizumoto H, Nishimura M, Tanaka R, Kudo R: Mutation of beta-catenin gene in endometrial cancer but not in associated hyperplasia. Med Electron Microsc. 2002, 35: 9-15. 10.1007/s007950200001CrossRefPubMed
17.
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C: Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA. 1998, 95: 8847-8851. 10.1073/pnas.95.15.8847CrossRefPubMed
18.
Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y: AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000, 24: 245-250. 10.1038/73448CrossRefPubMed
19.
Ihara A, Koizumi H, Hashizume R, Uchikoshi T: Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology. 1996, 23: 1441-1447.PubMed
20.
Brembeck FH, Rosario M, Birchmeier W: Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006, 16: 51-59. 10.1016/j.gde.2005.12.007CrossRefPubMed
21.
Lu Z, Ghosh S, Wang Z, Hunter T: Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2003, 4: 499-515. 10.1016/S1535-6108(03)00304-0CrossRefPubMed
22.
Forastiere AA, Burtness BA: Epidermal growth factor receptor inhibition in head and neck cancer: more insights, but more questions. J Clin Oncol. 2007, 25: 2152-2155. 10.1200/JCO.2007.10.9017CrossRefPubMed
23.
Lo HW, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung MC: Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 2005, 65: 338-348.PubMed
24.
Gordon MD, Nusse R: Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006, 281: 22429-22433. 10.1074/jbc.R600015200CrossRefPubMed
25.
Lilien J, Balsamo J: The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr Opin Cell Biol. 2005, 17: 459-465. 10.1016/j.ceb.2005.08.009CrossRefPubMed
26.
Willert K, Jones KA: Wnt signaling: Is the party in the nucleus?. Genes Dev. 2006, 20: 1394-1404. 10.1101/gad.1424006CrossRefPubMed
27.
Hoschuetzky H, Aberle H, Kemler R: Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol. 1994, 127: 1375-1380. 10.1083/jcb.127.5.1375CrossRefPubMed
28.
Moon HS, Choi EA, Park HY, Choi JY, Chung HW, Kim JI, Park WI: Expression and tyrosine phosphorylation of E-cadherin, beta- and gamma-catenin, and epidermal growth factor receptor in cervical cancer cells. Gynecol Oncol. 2001, 81: 355-359. 10.1006/gyno.2001.6163CrossRefPubMed
29.
Liu SY, Chang LC, Pan LF, Hung YJ, Lee CH, Shieh YS: Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol. 2007, 44: 277-285. 10.1016/j.oraloncology.2007.02.007CrossRefPubMed
30.
Ni CY, Murphy MP, Golde TE, Carpenter G: gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001, 294: 2179-2181. 10.1126/science.1065412CrossRefPubMed
31.
Prall F, Weirich V, Ostwald C: Phenotypes of invasion in sporadic colorectal carcinomaa related to aberrations of the adenomatous polyposis coli (APC) gene. Histopathology. 2007, 50: 218-230.
32.
Ilyas M: Wnt signalling and the mechanistic basis of tumour development. J Pathol. 2005, 205: 130-144. 10.1002/path.1692CrossRefPubMed
33.
Kajiguchi T, Lee S, Lee MJ, Trepel JB, Neckers L: KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia. Leuk Res. 2008, 32: 761-770. 10.1016/j.leukres.2007.08.023PubMedCentralCrossRefPubMed
34.
Camp ER, Yang A, Gray MJ, Fan F, Hamilton SR, Evans DB, Hooper AT, Pereira DS, Hicklin DJ, Ellis LM: Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target. Cancer. 2007, 109: 1030-1039. 10.1002/cncr.22490CrossRefPubMed
35.
Zinser GM, Leonis MA, Toney K, Pathrose P, Thobe M, Kader SA, Peace BE, Beauman SR, Collins MH, Waltz SE: Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. Cancer Res. 2006, 66: 11967-11974. 10.1158/0008-5472.CAN-06-2473CrossRefPubMed
36.
Coluccia AM, Vacca A, Duñach M, Mologni L, Redaelli S, Bustos VH, Benati D, Pinna LA, Gambacorti-Passerini C: Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007, 26: 1456-1466. 10.1038/sj.emboj.7601485PubMedCentralCrossRefPubMed
37.
Hamaguchi M, Matsuyoshi N, Ohnishi Y, Gotoh B, Takeichi M, Nagai Y: p60v-src causes tyrosine phosphorylation and inactivation of the N-cadherin-catenin cell adhesion system. EMBO J. 1993, 12: 307-314.PubMedCentralPubMed
38.
Shibata T, Gotoh M, Ochiai A, Hirohashi S: Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation. Biochem Biophys Res Commun. 1994, 203: 519-522. 10.1006/bbrc.1994.2213CrossRefPubMed
39.
Hu P, O'Keefe EJ, Rubenstein DS: Tyrosine phosphorylation of human keratinocyte beta-catenin and plakoglobin reversibly regulates their binding to E-cadherin and alpha-catenin. J Invest Dermatol. 2001, 117: 1059-1067. 10.1046/j.0022-202x.2001.01523.xCrossRefPubMed
40.
Kurdistani SK, Grunstein M: Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol. 2003, 4: 276-284. 10.1038/nrm1075CrossRefPubMed
41.
Jenuwein T, Allis CD: Translating the histone code. Science. 2001, 293: 1074-1080. 10.1126/science.1063127CrossRefPubMed
42.
Huber AH, Weis WI: The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell. 2001, 105: 391-402. 10.1016/S0092-8674(01)00330-0CrossRefPubMed
43.
Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H, Peifer M, Bejsovec A: Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature. 1998, 395: 604-608. 10.1038/26982CrossRefPubMed
44.
Brantjes H, Roose J, Wetering van De M, Clevers H: All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res. 2001, 29: 1410-1419. 10.1093/nar/29.7.1410PubMedCentralCrossRefPubMed
45.
Daniels DL, Weis WI: Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol. 2005, 12: 364-371. 10.1038/nsmb912CrossRefPubMed
46.
Bannister AJ, Kouzarides T: Histone methylation: recognizing the methyl mark. Methods Enzymol. 2004, 376: 269-288. full_textCrossRefPubMed
47.
Yochum GS, Cleland R, Goodman RH: A genome-wide screen for beta-catenin binding sites identifies a downstream enhancer element that controls c-Myc gene expression. Moll Cell Biol. 2008, 28: 7368-7379. 10.1128/MCB.00744-08.CrossRef
48.
Pukkila MJ, Virtaniemi JA, Kumpulainen EJ, Pirinen RT, Johansson RT, Valtonen HJ, Juhola MT, Kosma VM: Nuclear beta catenin expression is related to unfavourable outcome in oropharyngeal and hypopharyngeal squamous cell carcinoma. J Clin Pathol. 2001, 54: 42-47. 10.1136/jcp.54.1.42PubMedCentralCrossRefPubMed
49.
Gasparoni A, Chaves A, Fonzi L, Johnson GK, Schneider GB, Squier CA: Subcellular localization of beta-catenin in malignant cell lines and squamous cell carcinomas of the oral cavity. J Oral Pathol Med. 2002, 31: 385-394. 10.1034/j.1600-0714.2002.00108.xCrossRefPubMed
50.
51.
Tashiro E, Tsuchiya A, Imoto M: Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci. 2007, 98: 629-635. 10.1111/j.1349-7006.2007.00449.xCrossRefPubMed
52.
Akervall JA, Michalides RJ, Mineta H, Balm A, Borg A, Dictor MR, Jin Y, Loftus B, Mertens F, Wennerberg JP: Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer. 1997, 79: 380-389. 10.1002/(SICI)1097-0142(19970115)79:2<380::AID-CNCR22>3.0.CO;2-WCrossRefPubMed
53.
Bellacosa A, Almadori G, Cavallo S, Cadoni G, Galli J, Ferrandina G, Scambia G, Neri G: Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res. 1996, 2: 175-180.PubMed
Metadata
Title
Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer
Authors
Chien-Hsing Lee
Hsing-Wen Hung
Pei-Hsin Hung
Yi-Shing Shieh
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-64

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

Review

Leucine-rich repeat protein PRAME: expression, potential functions and clinical implications for leukaemia

Research

Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells

Research

Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells

Research

Evaluation of LMP1 of Epstein-Barr virus as a therapeutic target by its inhibition

Commentary

Broccoli, PTEN deletion and prostate cancer: where is the link?
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits