Context: BRAF mutations are common in papillary thyroid carcinomas (PTCs). By affecting the expression of genes critically related to the development and differentiation of thyroid cancer, they may influence the prognosis of these tumors. Objective: Our objective was to characterize the expression of thyroid-specific genes associated with BRAF mutation in PTCs. Design/Setting and Patients: We examined the expression of key markers of thyrocyte differentiation in 56 PTCs with BRAF mutations (BRAF-mut) and 37 with wild-type BRAF (BRAF-wt). Eight samples of normal thyroid tissue were analyzed as controls. Quantitative PCR was used to measure mRNA levels for the sodium/iodide symporter (NIS), apical iodide transporter (AIT-B), thyroglobulin (Tg), thyroperoxidase (TPO), TSH receptor (TSH-R), the transcription factor PAX8, and glucose transporter type 1 (Glut1). NIS protein expression and localization was also analyzed by immunohistochemistry. Results: mRNA levels for all thyroid-specific genes were reduced in all PTCs vs. normal thyroid tissues. NIS, AIT-B, Tg, and TPO expression was significantly lower in BRAF-mut tumors than in the BRAF-wt group. Glut-1 transcript levels were increased in all PTCs, and additional increases were noted in BRAF-mut tumors. In both tumor subsets, the NIS protein that was expressed was abnormally retained in the cytoplasm. Conclusion: BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. This effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mut PTCs.

MicroRNAs (miRNA) are crucial post‐transcriptional regulators of gene expression and control cell differentiation and proliferation. However, little is known about their targeting of specific developmental pathways. Hedgehog (Hh) signalling controls cerebellar granule cell progenitor development and a subversion of this pathway leads to neoplastic transformation into medulloblastoma (MB). Using a miRNA high‐throughput profile screening, we identify here a downregulated miRNA signature in human MBs with high Hh signalling. Specifically, we identify miR‐125b and miR‐326 as suppressors of the pathway activator Smoothened together with miR‐324‐5p, which also targets the downstream transcription factor Gli1. Downregulation of these miRNAs allows high levels of Hh‐dependent gene expression leading to tumour cell proliferation. Interestingly, the downregulation of miR‐324‐5p is genetically determined by MB‐associated deletion of chromosome 17p. We also report that whereas miRNA expression is downregulated in cerebellar neuronal progenitors, it increases alongside differentiation, thereby allowing cell maturation and growth inhibition. These findings identify a novel regulatory circuitry of the Hh signalling and suggest that misregulation of specific miRNAs, leading to its aberrant activation, sustain cancer development.

Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk‐adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c‐Myc overexpressing tumors) and in disease‐risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth‐inhibitory function. This property has been addressed for miR‐9 and miR‐125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies.