title: The PDCD4/miR-21 pathway in medullary thyroid carcinoma.
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.
authors.affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua 35121, Italy. Electronic address: gianmaria.pennelli@unipd.it.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Pennelli
authors.affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua 35121, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Galuppini
authors.affiliation: Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua 35128, Italy.
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.affiliation: Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua 35128, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cavedon
authors.affiliation: Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua 35128, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Bertazza
authors.affiliation: ARC-Net Research Centre, University of Verona, Verona 37134, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua 35121, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Guzzardo
authors.affiliation: Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Surgery Unit, University of Padua, Padua 35128, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pelizzo
authors.affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua 35121, Italy; Istituto Oncologico del Veneto, IOV-IRCCS, Padua 35128, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua 35128, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000097:blood / Q000235:genetics*; D001706:Biopsy; D002116:Calcitonin / Q000097:blood; D018278:Carcinoma, Neuroendocrine; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016601:RNA-Binding Proteins / Q000032:analysis*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000097:blood / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
keywords: Akt; Immunohistochemistry; Medullary thyroid cancer; MiR-21; PDCD4