Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation

Sage, Carlos le; Nagel, Remco; Egan, David A.; Schrier, Mariëtte; Mesman, Elly; Mangiola, Annunziato; Anile, C.; Maira, Giulio; Neri, Margherita; Ciafrè, Silvia Anna; Farace, Maria Giulia; Agami, Reuven

doi:10.1038/sj.emboj.7601790

Cited by 729 publications

(648 citation statements)

References 39 publications

(50 reference statements)

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“…Confirming the findings of He et al, 21 our results showed that miR146b, but not miR-146a, was overexpressed in papillary carcinoma. Also, similar to previous studies, 10,21,49 our results showed that the expression levels of miR-221 and miR-222 are closely coordinated. As both are clustered on X chromosome, 50 it is likely that they are encoded by a single polycistron, as was previously suggested.…”

Section: Discussionsupporting

confidence: 91%

“…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%

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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: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 72%

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

et al. 2008

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“…Recent reports revealed that the receptor tyrosine kinase Kit and the cyclin-dependent kinase (cdk) inhibitor, p27 kip1 , are both miR-221 and -222 functional targets (Felli et al, 2005;He et al, 2005;Poliseno et al, 2006;le Sage et al, 2007). Here we demonstrate that silencing of p27 kip1 , but not of Kit, increases TRAIL resistance.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

et al. 2008

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To define novel pathways that regulate susceptibility to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in non-small cell lung cancer (NSCLC), we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant NSCLC cells, levels of different miRs are increased, and in particular, miR-221 and -222. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. Indeed, transfection with anti-miR-221 and -222 rendered CALU-1-resistant cells sensitive to TRAIL. Conversely, H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3 0 -UTR of Kit and p27 kip1 mRNAs, but interfere with TRAIL signaling mainly through p27 kip1 . In conclusion, we show that high expression levels of miR-221 and -222 are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets or diagnostic tool for TRAIL resistance in NSCLC.

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“…Paradoxically, miR-222 was previously regarded as oncogene in some reports because it could enhance some tumour cell growth by targeting CDK inhibitor p27 in vitro, and was found to be upregulated in HCC and some other types of cancers 42,51,52 ; however, its tumourpromoting role was rarely validated in vivo. Our data support miR-222 to be a tumour suppressor in HCC by controlling the stemness and tumorigenicity of a2d1 þ TICs, further confirming that the roles of miRNAs are cell context-dependent 50 .…”

Section: Discussionmentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

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Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation

Cited by 729 publications

References 39 publications

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

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