MicroRNA deregulation in human thyroid papillary carcinomas

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in a wide range of basic processes such as cell proliferation, development, apoptosis and stress response. It has recently been found that they are also abnormally expressed in many types of human cancer. We analyzed the genome-wide miRNA expression profile in human thyroid papillary carcinomas (PTCs) using a microarray (miRNACHIP microarray) containing hundreds of human precursor and mature miRNA oligonucleotide probes. Using this approach, we found an aberrant miRNA expression profile that clearly differentiates PTCs from normal thyroid tissues. In particular, a significant increase in miRNA (miR)-221, -222 and -181b was detected in PTCs in comparison with normal thyroid tissue. These results were further confirmed by northern blot and quantitative RT-PCR analyses. Moreover, RT-PCR revealed miR-221, -222 and -181b overexpression in fine needle aspiration biopsies corresponding to thyroid nodules, which were eventually diagnosed as papillary carcinomas after surgery. Finally, miR-221, -222 and -181b overexpression was also demonstrated in transformed rat thyroid cell lines and in mouse models of thyroid carcinogenesis. Functional studies, performed by blocking miR-221 function and by overexpressing miR-221 in human PTC-derived cell lines, suggest a critical role of miR-221 overexpression in thyroid carcinogenesis. In conclusion, these data, taken together, indicate an miRNA signature associated with PTCs, and suggest miRNA deregulation as an important event in thyroid cell transformation.

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

“…To identify the onco-miRNAs regulated by AP-1 in response to the RAS oncoprotein, we analysed the RASand AP-1-dependent expression of several members of the earlier reported miRNA signatures of papillary thyroid carcinoma (He et al, 2005;Pallante et al, 2006), in the A-FOS, compared with the parental cell line (data not shown). QRT-PCR showed that miR-21 was induced by RAS, about fivefold in the FRTL-5/ER-RAS cell line, compared with less than twofold in the A-FOS cells (Figure 3a).…”

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

“…21,22,40 Ten cases each of papillary thyroid carcinoma (eight classical and two follicular variant) and follicular adenoma were analyzed using paraffin-embedded materials. All cases showed uniformly high miRNA quality, with C t values for control U6 RNA RT-PCR clustering within o3 amplification cycles for all samples (Figure 1a).…”

“…In contrast, overexpression of a selected number of miRNA over normal thyroid was found in follicular carcinoma and in papillary carcinoma. Four miRNAs (miR-192, miR-197, miR-328, and miR-346) were found to show increased expression in follicular carcinoma, whereas a nonoverlapping group of miRNAs was found to have increased expression in papillary carcinoma, including miR-221, miR-222, miR-146, 21,22,40 miR181b, 22 miR-155, miR-187 40 etc.…”

“…By using array-based technology and reverse transcription (RT)-PCR, the global miRNA expression profiles as well as the level of individual miRNA species have been analyzed in various human cancers, and aberrant miRNA expression was found in all tumor types studied to date, including hematological malignancies, 6 lymphoma, 7 melanoma, 8 glioblastoma, 9,10 as well as epithelial cancers from lung, 11,12 breast, 13,14 colon, 15,16 liver, 17,18 thyroid, [19][20][21][22] pancreas [23][24][25][26] etc. When compared to their normal-tissue counterparts, both overexpression and underexpression of miRNA has been observed, with decreased expression appearing to be more common in some studies, 8,27 leading to the hypothesis that oncogenes might be target genes for these miRNAs.…”

“…This cancer biology aspect of miRNA has been the subject of multiple recent reviews. 3,5,[28][29][30][31][32][33][34][35][36][37][38] In thyroid tumors, miRNA changes have been found in papillary thyroid carcinoma, 21,22,39 follicular carcinoma, 19 and anaplastic carcinoma. 20 In anaplastic carcinoma, the main changes appeared to be underexpression, and a significant decrease of miR-30d, miR-125b, miR-26a, and miR-30a-5p expression was described in comparison to normal thyroid tissue.…”