MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle

Visone, Rosa; Russo, Lucía; Pallante, Pierlorenzo; Martino, Ivana De; Ferraro, Angelo; Leone, Vincenza; Borbone, Eleonora; Petrocca, Fabio; Alder, Hansjüerg; Croce, Carlo M.; Fusco, Alfredo

doi:10.1677/erc-07-0129

Cited by 383 publications

(304 citation statements)

References 33 publications

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“…In contrast, although miR-146b, -221, and -222 were all upregulated in papillary thyroid carcinoma, our data suggest that they are regulated differently in cancer. Consistent with this notion, miR-221 and miR-222 have been implicated in multiple tumor types, 10,39,49,[51][52][53] including glioblastoma and leukemia, and miR-146 has only been associated with papillary thyroid carcinoma and melanoma. 8,21,22 In summary, we showed that when compared to normal thyroid tissue, miR-146b, miR-221, and miR-222 were overexpressed in almost all cases of papillary thyroid carcinoma but not in follicular adenoma or hyperplastic thyroid nodules.…”

Section: Discussionmentioning

confidence: 72%

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

et al. 2008

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MicroRNA (miRNA) microarray analysis has consistently found altered expression of miRNAs in thyroid tumors, suggesting their roles in thyroid carcinogenesis. To explore whether this differential expression can be used as a diagnostic tool in surgical pathology and fine-needle aspirate (FNA) specimens, the expression of selected miRNA was evaluated by quantitative RT-PCR, using total RNA from 84 formalin-fixed paraffin-embedded tissues and 40 ex vivo aspirate specimens. miRNA from all paraffin-embedded tissues and all but one FNA sample were found to be analyzable, with paraffin sections yielding better miRNA quality. Preliminary analysis of 6 miRNAs in 10 papillary thyroid carcinoma and 10 follicular adenoma identified significant overexpression of miR-146b, -221, and -222 in papillary thyroid carcinoma (Po0.02), but not miR-146a, -155, or -187 (P40.08). The expression of these first three miRNAs was examined in a series of 5 normal thyroid, 11 hyperplastic nodules, 24 follicular adenoma, 27 classical papillary thyroid carcinoma, 5 follicular variant papillary thyroid carcinoma, 2 follicular carcinoma, and 10 encapsulated follicular lesions with partial nuclear features of papillary carcinoma. Results showed miR-146b to be most consistently overexpressed in both classical papillary carcinoma and follicular variants, whereas all other groups showed lower expression at a similar level (Po0.001 for pair-wise comparisons between papillary carcinoma and all other groups). Follicular lesions with partial features of papillary carcinoma all showed low miR-146b levels similar to other non-papillary carcinoma groups, suggesting that they are biologically distinctive from papillary carcinoma. miR-221 and miR-222 also showed higher expression in papillary carcinoma, but with substantial overlaps with the other groups. When applied to 40 FNA samples of various lesions, only miR-146b and miR-222 persisted as distinguishing markers for papillary carcinoma. We concluded that miRNAs, particularly miR-146b, might potentially be adjunct markers for diagnosing papillary thyroid carcinoma in both FNA and surgical pathology specimens.

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Section: Discussionmentioning

confidence: 72%

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

et al. 2008

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“…In fact, miR-21 was shown to directly target the tumor suppressor PTEN (encoding a phosphatase that can inhibit growth and/or survival pathways) in cholangiocarcinoma cells (Meng et al, 2007). Moreover, the miR-221/222 cluster, upregulated in thyroid and prostate cancer, was shown to target the p27 kip1 protein, a critical negative regulator of the cell cycle (Galardi et al, 2007;Visone et al, 2007). Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions regulating the miRNA expression.…”

Section: Introductionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

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“…Several components account for the reduced p27 protein levels in thyroid malignant neoplasias: both PTEN and PTPRJ, whose expression is drastically reduced in thyroid malignant neoplasias , increase the stability of the p27 protein. Recent data show increased miR221 and 222 levels in PTCs that correlate with low levels of p27 (Visone et al 2007). However, a causal link between p27 impairment and thyroid carcinogenesis has not been established yet.…”

Section: Introductionmentioning

confidence: 99%

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

Fedele¹,

Palmieri²,

Chiappetta³

et al. 2009

Endocrine-Related Cancer

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Impairment of the p27 kip1 function, caused by a drastic reduction of its expression or cytoplasmic mislocalization, has been frequently observed in thyroid carcinomas. To understand the role of p27 kip1 impairment in thyroid carcinogenesis, we investigated the consequences of the loss of p27 kip1 expression in the context of a mouse modeling of papillary thyroid cancer, expressing the TRK-T1 oncogene under the transcriptional control of thyroglobulin promoter. We found that double mutant mice homozygous for a p27 kip1 null allele (TRK-T1/p27 K/K ) display a higher incidence of papillary thyroid carcinomas, with a shorter latency period and increased proliferation index, compared with p27 kip1 wild-type compounds (TRK-T1/p27 C/C ). Consistently, double mutant mice heterozygous for a p27 kip1 null allele (TRK-T1/p27 C/K ) show an incidence of thyroid carcinomas that is intermediate between TRK-T1/p27 K/K and TRK-T1/p27 C/C mice. Therefore, our findings suggest a dose-dependent role of p27 kip1 function in papillary thyroid cancer development.

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MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle

Cited by 383 publications

References 33 publications

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

Regulation of microRNA expression by HMGA1 proteins

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

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