期刊
CLINICAL CANCER RESEARCH
卷 17, 期 6, 页码 1317-1330出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-2320
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资金
- Dutch Cancer Society [RUG 2004-3161]
- The Netherlands Bioinformatics Centre (NBIC)
- Netherlands Genomics Initiative (NGI)
- European Union [LSHG-CT-2004-512018]
Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer. Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N-0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways. Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-beta, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N-0, and two pathways (beta-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P < 0.001) were involved in beta-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-beta and beta-catenin) confirmed that the TGF-beta pathway (positivity of Smad4) was related to N-0 (OR:0.20, 95% CI: 0.06-0.66) and the beta-catenin pathway (p120 positivity) to N+ (OR: 1.79, 95% CI: 1.05-3.05). Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-beta and p120-associated noncanonical beta-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res; 17(6); 1317-30. (C)2011 AACR.
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