microRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome.

Background: microRNAs (miRNAs) are involved in the pathogenesis of human cancers, including medullary thyroid carcinomas (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in hereditary (hMTC) and sporadic (sMTC) MTC patients. Methods: We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative RT-PCR in 34 cases of sMTC, 6 cases of hMTC and 2 cases of C-cell hyperplasia (CCH). We also analyzed the immunohistochemical expression of PDCD4, a miR-21 gene target. sMTC (n=34) were genotyped for somatic RET and RAS mutations. Disease status was defined on the basis of the concentration of serum calcitonin at the latest follow-up and other parameters as indicated in the results. Results: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323 and 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183 and 10.1 for miR-375, p<0.0001). PDCD4 expression was significantly down-regulated in MTC samples, consistent with miR-21 upregulation. Significantly lower miR-127 levels were observed in sMTC carrying somatic RET mutations in comparison to sMTC carrying a wild-type RET. In sporadic and familial MTC, the miR-224 upregulation correlated with the absence of node metastases, lower stages at diagnosis, and with biochemical cure during follow-up. Conclusions: miRNAs are significantly dysregulated in MTC, and this dysregulation is probably an early event in C-cell carcinogenesis. miR-224 upregulation could represent a prognostic biomarker associated with a better outcome in MTC patients.