Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer

Clin Cancer Res. 2011 Mar 15;17(6):1317-30. doi: 10.1158/1078-0432.CCR-10-2320. Epub 2011 Mar 8.

Abstract

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-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N(0), and two pathways (β-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 N(0) and N(+) tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N(0) (OR: 0.20, 95% CI: 0.06-0.66) and the β-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-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Catenins / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphatic Metastasis
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Transforming Growth Factor beta / metabolism*
  • Uterine Cervical Neoplasms / metabolism*
  • beta Catenin / metabolism*

Substances

  • Catenins
  • Transforming Growth Factor beta
  • beta Catenin
  • delta catenin