The PDCD4/miR-21 pathway in medullary thyroid carcinoma

Hum Pathol. 2015 Jan;46(1):50-7. doi: 10.1016/j.humpath.2014.09.006. Epub 2014 Oct 2.

Abstract

Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in tumorogenesis. MicroRNA-21 (miR-21) specifically targets PDCD4, and recent studies suggest that PDCD4 is also regulated by Akt (antiapoptotic regulator within phosphatidylinositol 3-kinase). Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer, and disease stage at diagnosis represents the main prognostic indicator. A consecutive series of 64 MTCs was considered. REarranged during Transfection (RET) and rat sarcoma (RAS) mutation status was assessed by direct sequencing. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-21. PDCD4 and Ki-67 immunostaining was performed with an automated platform. Immunoblot analysis of PI3K/Akt pathway was done on thyroid tissues. MTCs were consistently associated with miR-21 up-regulation (P < .0016) and featured significant PDCD4 nuclear down-regulation. An inverse correlation emerged between miR-21 overexpression and PDCD4 down-regulation (P = .0013). At enrollment, high miR-21 levels were associated with high calcitonin levels (P = .0003), lymph node metastases (P = .001), and advanced stages (P = .0003). At the end of follow-up, high miR-21 levels were associated with biochemically persistent disease (P = .0076). At enrollment, instead, PDCD4 nuclear down-regulation was associated with high calcitonin levels (P = .04), more advanced stages of disease (P < .01), and persistent disease after the follow-up (P = .02). p-Akt was more expressed in RAS-mutated MTC than in nonmutated cancers and normal tissue. This study showed, in MTCs, that miR-21 regulates PDCD4 expression and also that the miR-21/PDCD4 pathway correlates with clinicopathological variables and prognosis. Further studies should investigate the role of miR-21 as a prognostic biomarker and the feasibility of using PDCD4-restoring strategies as a therapeutic approach to MTC.

Keywords: Akt; Immunohistochemistry; Medullary thyroid cancer; MiR-21; PDCD4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis Regulatory Proteins / analysis*
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics*
  • Biopsy
  • Calcitonin / blood
  • Carcinoma, Neuroendocrine
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / analysis
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / analysis
  • Proto-Oncogene Proteins c-ret / genetics
  • RNA-Binding Proteins / analysis*
  • Real-Time Polymerase Chain Reaction
  • Retrospective Studies
  • Signal Transduction*
  • Thyroid Neoplasms / blood
  • Thyroid Neoplasms / chemistry*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / mortality
  • Thyroid Neoplasms / pathology
  • Up-Regulation
  • Young Adult
  • ras Proteins / genetics

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • Ki-67 Antigen
  • MIRN21 microRNA, human
  • MicroRNAs
  • PDCD4 protein, human
  • RNA-Binding Proteins
  • Calcitonin
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Proto-Oncogene Proteins c-akt
  • ras Proteins

Supplementary concepts

  • Thyroid cancer, medullary