The PDCD4/miR-21 pathway in medullary thyroid carcinoma

• Published in: Human pathology Vol. 46; no. 1; pp. 50 - 57
• Main Authors: Pennelli, Gianmaria, Galuppini, Francesca, Barollo, Susi, Cavedon, Elisabetta, Bertazza, Loris, Fassan, Matteo, Guzzardo, Vincenza, Pelizzo, Maria Rosa, Rugge, Massimo, Mian, Caterina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015; Elsevier Limited
• Subjects: Adult; Aged; Aged, 80 and over; Akt; 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; Genes; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Ki-67 Antigen - analysis; Kinases; Male; Medical prognosis; Medullary thyroid cancer; MicroRNAs; MicroRNAs - genetics; Middle Aged; MiR-21; Mutation; Neoplasm Staging; Pathology; PDCD4; Phenotype; Phosphorylation; Polymerase chain reaction; Proteins; Proto-Oncogene Proteins c-akt - analysis; Proto-Oncogene Proteins c-ret - genetics; ras Proteins - genetics; Real-Time Polymerase Chain Reaction; Retrospective Studies; RNA-Binding Proteins - analysis; Signal Transduction; Studies; Thyroid cancer; Thyroid Neoplasms - blood; Thyroid Neoplasms - chemistry; Thyroid Neoplasms - genetics; Thyroid Neoplasms - mortality; Thyroid Neoplasms - pathology; Up-Regulation; Young Adult; Immunohistochemistry; PDCD4; Akt; MiR-21; Medullary thyroid cancer
• ISSN: 0046-8177; 1532-8392; 1532-8392
• DOI: 10.1016/j.humpath.2014.09.006

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.