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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 11; pp. 5656 - 5664
• Main Authors: COHEN, Greg, MUSTAFI, Reba, YERIAN, Lisa, TRETIAKOVA, Maria, WEIHUA YUAN, OBARA, Piotr, KHARE, Sharad, SINICROPE, Frank A, FICHERA, Alessandro, BOSS, Gerry R, CARROLL, Robert, BISSONNETTE, Marc, CHUMSANGSRI, Anusara, LITTLE, Nathaniel, NATHANSON, Jeff, CERDA, Sonia, JAGADEESWARAN, Sujatha, DOUGHERTY, Urszula, JOSEPH, Loren, HART, John
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Growth Processes - physiology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cyclin D1 - biosynthesis; Cyclin D1 - genetics; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes, ras; Humans; Male; Medical sciences; Middle Aged; Mutation; Pharmacology. Drug treatments; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proliferating Cell Nuclear Antigen - biosynthesis; Proliferating Cell Nuclear Antigen - genetics; Proto-Oncogene Proteins B-raf - genetics; Receptor, Epidermal Growth Factor - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Up-Regulation; Colonic disease; Human; Signal transduction; Growth factor receptor; Premalignant lesion; Digestive system; Digestive diseases; Intestinal disease; Colon premalignant lesion; Epidermal growth factor receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-0308

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.