Methylation status of insulin-like growth factor-binding protein 7 concurs with the malignance of oral tongue cancer

J Exp Clin Cancer Res. 2015 Feb 24;34(1):20. doi: 10.1186/s13046-015-0138-5.


Background: Aberrant insulin-like growth factor-binding protein 7 (IGFBP-7) expression has been found in various cancers such as prostate, breast, and colon. IGFBP-7 induced the apoptosis of tumor and potentially predicted the clinical outcome in some cancers is further demonstrated. This study investigates the causes and underlying mechanisms of aberrant IGFBP-7 expression in unravelling head and neck squamous cell carcinoma (HNSCC).

Methods: A total of 47 oral tongue cancer patient samples were primarily analyzed for the methylation status in 5' region of IGFBP-7 by methylation-specific PCR (MS-PCR). Subsequently the invasion, overexpression, and knockdown of IGFBP-7 in the HNSCC A253 invasive subpopulation were employed to examine the effect of IGFBP-7. The epithelial-mesenchymal transition (EMT) marker genes and AKT/GSK3β/β-catenin signaling were further evaluated by Western blot for the understanding the role of aberrant IGFBP-7 expression and thereof putative mechanism.

Results: EMT expressed in the invasive subpopulation of HNSCC cell lines (A253 and RPMI 2650) was contemporary with the down-regulation of IGFBP-7. After treatment with 5-AZA-2' deoxycytidine, the de-methylated CpG sites in the 5' region of IGFBP-7 were observed and IGFBP-7 mRNA expression was also restored. Accordingly, re-expression IGFBP-7 in invasive subpopulation of A253 could induce the mesenchymal-epithelial transition (MET) and concurrently inhibited the cell invasion. Moreover, IGFBP-7 methylation status of 47 oral tongue tumors showed a positive correlation to invasive depth of the tumor, loco-regional recurrence, and cancer sequence.

Conclusions: IGFBP-7 can alter EMT relative marker genes and suppress cell invasion in A253 cell through AKT/GSK3β/β-catenin signaling. The epigenetic control of IGFBP-7 in the invasion and metastasis of HNSCC was reported, suggesting that IGFBP-7 could be a prognostic factor for the probability of invasion and a therapeutic remedy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line, Tumor
  • DNA Methylation*
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / genetics*
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Tongue Neoplasms / genetics*
  • Tongue Neoplasms / metabolism
  • Tongue Neoplasms / mortality
  • Tongue Neoplasms / pathology*
  • Tongue Neoplasms / therapy
  • Tumor Burden


  • Insulin-Like Growth Factor Binding Proteins
  • insulin-like growth factor binding protein-related protein 1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3