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DNA methylation of MAPK signal-inhibiting genes in papillary thyroid carcinoma

Eun Kyung Lee1, Ki-Wook Chung, Sun Kyung Yang

  • 1Division of Endocrine surgery, Department of Surgery, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea. surgeonckw@amc.seoul.kr.

Anticancer Research
|November 14, 2013
PubMed
Abstract

Insights

DNA methylation impacts gene expression in thyroid cancer. SERPINA5 (serpin peptidase inhibitor A member 5) methylation was linked to BRAF mutations in papillary thyroid cancer (PTC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Thyroid cancer, particularly papillary thyroid cancer (PTC), is a significant health concern.
  • Understanding the molecular mechanisms, including epigenetic alterations, is crucial for diagnosis and treatment.
  • Mitogen-activated protein kinase (MAPK) signaling pathways are frequently dysregulated in various cancers.

Purpose of the Study:

  • To investigate the DNA methylation status of key MAPK signal-inhibiting genes: dual-specificity phosphatase 4 (DUSP4), dual-specificity phosphatase 6 (DUSP6), and serpin peptidase inhibitor A member 5 (SERPINA5) in thyroid cancer.
  • To determine the relationship between the methylation status of these genes and their expression levels in thyroid cancer.
  • To explore the association between SERPINA5 methylation and specific genetic mutations, such as BRAF, in papillary thyroid cancer.

Main Methods:

  • Analysis of 76 papillary thyroid cancer (PTC) tissues and three human thyroid cancer cell lines (TPC1, WRO82-1, XTC).
  • Gene expression profiling using reverse transcription-polymerase chain reaction (RT-PCR).
  • DNA methylation analysis using methylation-specific PCR (MSP).
  • Treatment with a demethylating agent (5'-aza-2'-deoxycytidine) to assess functional impact on gene expression.

Main Results:

  • DUSP4 and DUSP6 exhibited increased expression with unmethylated promoter regions in all tested cell lines.
  • SERPINA5 gene expression was decreased and its promoter DNA was methylated in the TPC1 cell line.
  • Demethylation treatment restored SERPINA5 gene expression, confirming a regulatory role of DNA methylation.
  • In 82.9% of PTC tissues, SERPINA5 promoter DNA was methylated.
  • SERPINA5 promoter methylation was significantly associated with a higher rate of BRAF mutations in PTC tissues (OR=3.573, p=0.031).

Conclusions:

  • SERPINA5, a MAPK signal-inhibiting gene, shows decreased expression in thyroid cancer cells, regulated by DNA methylation.
  • DNA methylation of the SERPINA5 promoter is a frequent event in papillary thyroid cancer.
  • SERPINA5 promoter methylation is associated with an increased prevalence of BRAF mutations in PTC, suggesting a potential link in oncogenesis.
Keywords:
SERPINA5Thyroid cancermethylation

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