Wnt/β‑catenin pathway activation and silencing of the APC gene in HPV‑positive human cervical cancer‑derived cells

Mol Med Rep. 2018 Jan;17(1):200-208. doi: 10.3892/mmr.2017.7853. Epub 2017 Oct 20.

Abstract

Although persistent infections with high‑risk human papilloma virus (HPV) constitute the most significant cofactor for the development of cervical cancer, they are insufficient on their own. Mutations or epigenetic inactivation of the tumor suppressor adenomatous polyposis coli (APC), the two acting as prominent oncogenic mechanisms in a number of types of cancer, are frequently associated with aberrant activation of the Wnt/β‑catenin pathway. According to these observations, it was hypothesized that APC alteration may lead to β‑catenin deregulation and the abnormal expression of direct targets of the Wnt pathway in HPV‑infected cervical cancer cells. The present study confirmed that the stabilization of β‑catenin correlates with enhanced transcriptional activity of the β‑catenin/T‑cell factor complex in cervical cancer cell lines. Sequence analysis of the 'hot‑spot' in the mutation cluster region did not exhibit genetic alterations that may be associated with APC gene inactivation. In addition, it was identified that there was a good correlation with the hypermethylation status of the APC promoter 1A and the abnormal accumulation of endogenous β‑catenin in cell lines and biopsies infected with HPV16, although not HPV18. Removal of the epigenetic markers led to an increase in APC levels and a reduction of β‑catenin expression in two transcriptional targets of the Wnt pathway: Matrix metalloproteinase‑7 and vascular endothelial growth factor. The present study suggested that the increase in Wnt activity in certain cervical cancer‑derived cells may be associated with an alteration in the methylation status of the APC gene promoter 1A.

MeSH terms

  • Biopsy
  • Cell Line, Tumor
  • DNA Methylation
  • DNA Mutational Analysis
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genes, APC*
  • Genes, Reporter
  • Humans
  • Mutation
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / virology
  • Promoter Regions, Genetic
  • Transcription, Genetic
  • Uterine Cervical Neoplasms / etiology*
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • beta Catenin