Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci

被引:46
作者
Cohen, Greg
Mustafi, Reba
Chumsangsri, Anusara
Little, Nathaniel
Nathanson, Jeff
Cerda, Sonia
Jagadeeswaran, Suiatha
Dougherty, Urszula
Joseph, Loren
Hart, John
Yerian, Lisa
Tretiakova, Maria
Yuan, Weihua
Obara, Piotr
Khare, Sharad
Sinicrope, Frank A.
Fichera, Alessandro
Boss, Gerry R.
Carroll, Robert
Bissonnette, Marc
机构
[1] Univ Chicago, Dept Med, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Surg, Chicago, IL 60637 USA
[4] Univ Illinois, Dept Med, Chicago, IL USA
[5] Mayo Clin, Dept Med, Rochester, MN USA
[6] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA
关键词
D O I
10.1158/0008-5472.CAN-05-0308
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >= 2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4 fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/-+/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.
引用
收藏
页码:5656 / 5664
页数:9
相关论文
共 56 条
  • [1] TRANSFORMING P21(RAS) MUTANTS AND C-ETS-2 ACTIVATE THE CYCLIN D1 PROMOTER THROUGH DISTINGUISHABLE REGIONS
    ALBANESE, C
    JOHNSON, J
    WATANABE, G
    EKLUND, N
    VU, D
    ARNOLD, A
    PESTELL, RG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (40) : 23589 - 23597
  • [2] EPIDERMAL GROWTH FACTOR-RELATED PEPTIDES AND THEIR RELEVANCE TO GASTROINTESTINAL PATHOPHYSIOLOGY
    BARNARD, JA
    BEAUCHAMP, RD
    RUSSELL, WE
    DUBOIS, RN
    COFFEY, RJ
    [J]. GASTROENTEROLOGY, 1995, 108 (02) : 564 - 580
  • [3] BRAF mutations in aberrant crypt foci and hyperplastic polyposis
    Beach, R
    Chan, AOO
    Wu, TT
    White, JA
    Morris, JS
    Lunagomez, S
    Broaddus, RR
    Issa, JPJ
    Hamilton, SR
    Rashid, A
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2005, 166 (04) : 1069 - 1075
  • [4] ROLE OF ABERRANT CRYPT FOCI IN UNDERSTANDING THE PATHOGENESIS OF COLON-CANCER
    BIRD, RP
    [J]. CANCER LETTERS, 1995, 93 (01) : 55 - 71
  • [5] Bissonnette M, 2000, CANCER RES, V60, P4602
  • [6] Aberrant crypt foci in patients with neoplastic and nonneoplastic colonic disease
    Bouzourene, H
    Chaubert, P
    Seelentag, W
    Bosman, FT
    Saraga, E
    [J]. HUMAN PATHOLOGY, 1999, 30 (01) : 66 - 71
  • [7] DIFFERENTIAL EXPRESSION OF EPIDERMAL GROWTH FACTOR-RELATED PROTEINS IN HUMAN COLORECTAL TUMORS
    CIARDIELLO, F
    KIM, N
    SAEKI, T
    DONO, R
    PERSICO, MG
    PLOWMAN, GD
    GARRIGUES, J
    RADKE, S
    TODARO, GJ
    SALOMON, DS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (17) : 7792 - 7796
  • [8] Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells
    Coffey, RJ
    Hawkey, CJ
    Damstrup, L
    GravesDeal, R
    Daniel, VC
    Dempsey, PJ
    Chinery, R
    Kirkland, SC
    DuBois, RN
    Jetton, TL
    Morrow, JD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (02) : 657 - 662
  • [9] Most effective colon cancer chemopreventive agents in rats:: A systematic review of aberrant crypt foci and tumor data, ranked by potency
    Corpet, DE
    Taché, S
    [J]. NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, 2002, 43 (01): : 1 - 21
  • [10] Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis
    Din, FVN
    Dunlop, MG
    Stark, LA
    [J]. BRITISH JOURNAL OF CANCER, 2004, 91 (02) : 381 - 388