TY - JOUR
T1 - Synchronous alterations of Wnt and epidermal growth factor receptor signaling pathways through aberrant methylation and mutation in non-small cell lung cancer
AU - Suzuki, Makoto
AU - Shigematsu, Hisayuki
AU - Nakajima, Takahiro
AU - Kubo, Rieko
AU - Motohashi, Shinichiro
AU - Sekine, Yasuo
AU - Shibuya, Kiyoshi
AU - Iizasa, Toshihiko
AU - Hiroshima, Kenzo
AU - Nakatani, Yukio
AU - Gazdar, Adi F.
AU - Fujisawa, Takehiko
PY - 2007/10/15
Y1 - 2007/10/15
N2 - Purpose: The Wnt and epidermal growth factor receptor (EGFR) signaling pathways play crucial roles in the pathogenesis of a variety of malignant tumors. Although the details of each cascade are understood, very little is known about their collective effects in non-small cell lung cancer (NSCLC). Experimental Design: At otal of 238 NSCLC samples were examined for methylation of Wnt antagonists [secreted frizzled-related protein (sFRP)-1, sFRP-2, sFRP-5, Wnt inhibitory factor-1, and Dickkopf-3] and for EGFR and KRAS mutations. Protein expression levels of β-catenin were assayed in 91 of the 238 NSCLCs. Results: We found that (a) aberrant methylation of Wnt antagonists is common in NSCLCs; (b) methylation of sFRP-2 is more prevalent in females, nonsmokers, and adenocarcinoma cases; (c) Dickkopf-3 methylation is significantly associated with a poor prognosis in adenocarcinomas; (d) there is a positive correlation between activated EGFR mutation and nuclear accumulation of β-catenin; (e) KRAS mutation and aberrant methylation of Wnt antagonists are positively correlated; and (f) EGFR mutation is significantly associated with a good prognosis in tumors lacking methylated Wnt antagonist genes. Conclusions: These results contribute to a better understanding of the cross-talk between the Wnt and EGFR signaling pathways and help foster development of chemotherapeutic treatments in NSCLCs.
AB - Purpose: The Wnt and epidermal growth factor receptor (EGFR) signaling pathways play crucial roles in the pathogenesis of a variety of malignant tumors. Although the details of each cascade are understood, very little is known about their collective effects in non-small cell lung cancer (NSCLC). Experimental Design: At otal of 238 NSCLC samples were examined for methylation of Wnt antagonists [secreted frizzled-related protein (sFRP)-1, sFRP-2, sFRP-5, Wnt inhibitory factor-1, and Dickkopf-3] and for EGFR and KRAS mutations. Protein expression levels of β-catenin were assayed in 91 of the 238 NSCLCs. Results: We found that (a) aberrant methylation of Wnt antagonists is common in NSCLCs; (b) methylation of sFRP-2 is more prevalent in females, nonsmokers, and adenocarcinoma cases; (c) Dickkopf-3 methylation is significantly associated with a poor prognosis in adenocarcinomas; (d) there is a positive correlation between activated EGFR mutation and nuclear accumulation of β-catenin; (e) KRAS mutation and aberrant methylation of Wnt antagonists are positively correlated; and (f) EGFR mutation is significantly associated with a good prognosis in tumors lacking methylated Wnt antagonist genes. Conclusions: These results contribute to a better understanding of the cross-talk between the Wnt and EGFR signaling pathways and help foster development of chemotherapeutic treatments in NSCLCs.
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U2 - 10.1158/1078-0432.CCR-07-0591
DO - 10.1158/1078-0432.CCR-07-0591
M3 - Article
C2 - 17947472
AN - SCOPUS:35948990450
SN - 1078-0432
VL - 13
SP - 6087
EP - 6092
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -