miR-191 downregulation plays a role in thyroid follicular tumors through CDK6 targeting

miR-191 expression is frequently altered in several neoplasias, being upregulated in some, such as pancreatic, colon, lung and prostate carinomas, and downregulated in others, such as severe medulloblastomas and melanomas. I have investigated the expression of miR-191 in thyroid neoplasias. In my thesis I report that miR-191 is downregulated in follicular adenomas and carcinomas, with a reduction that is almost 2-fold higher in follicular carcinomas with respect to adenomas. Conversely it is upregulated in thyroid carcinomas of the papillary histotype (PTCs), in comparison with the normal thyroid tissue. Consistent with a putative tumour suppressor role of miR-191 in the development of thyroid neoplasias of the follicular histotype, functional studies showed that restoration of miR-191 expression in a follicular thyroid cancer cell line reduces cell growth and migration rate. Furthermore, I found that miR-191 negatively regulates the expression of CDK6 protein, involved in cell cycle control, without changing the CDK6 mRNA level and decreases the activity of a luciferase reporter construct containing the CDK6-3'untranslated region. These results demonstrate that miR-191 regulates CDK6 at the posttranscriptional level, resulting in inhibition of cell proliferation and migration of the follicular thyroid carcinoma cell line; I will show that restoration of miR-191 expression reduces cell proliferation leading to an increased number of the cells in the G1 phase of the cell cycle. Finally, in follicular adenomas and carcinomas, we immunohistochemically detected CDK6 over-expression, suggesting that miR-191 may have a pathogenic role in thyroid cancer by controlling CDK6 expression

Let-7a Down-Regulation Plays a Role in Thyroid Neoplasias of Follicular Histotype Affecting Cell Adhesion and Migration through Its Ability to Target the<i>FXYD5</i>(Dysadherin) Gene

n/

miR-191 down-regulation plays a role in thyroid follicular tumors through CDK6 targeting.

CONTEXT: Well-differentiated thyroid carcinomas include papillary (PTC) and follicular (FTC) carcinomas. FTC is usually a more aggressive form of cancer than the more common papillary type. miR-191 expression is frequently altered in several neoplasias, being up-regulated in some cases, such as pancreatic carcinomas, and down-regulated in other carcinomas, such as melanomas. OBJECTIVE: The objective was to evaluate the expression and the role of miR-191 in thyroid carcinogenesis. DESIGN: The expression of miR-191 was analyzed in tissues from patients with follicular adenoma (n = 24), FTC (n = 24), PTC (n = 15), anaplastic thyroid carcinoma (n = 8), and the follicular variant of PTC (n = 6) compared with normal thyroid tissues by quantitative RT-PCR. miR-191 expression was restored in the follicular thyroid cell line WRO, and the effects on cell proliferation, migration, and target expression were evaluated. RESULTS: miR-191 is down-regulated in follicular adenoma, FTC, and follicular variant of PTC. We identified CDK6, a serine-threonine kinase involved in the control of cell cycle progression, as a novel target of miR-191. Restoration of miR-191 expression in WRO cells reduces cell growth and migration rate on vitronectin. CDK6 overexpression, correlated with miR-191 down-regulation, was found in follicular adenoma and FTC, suggesting a role of miR-191 down-regulation in the generation of these neoplasias. CONCLUSIONS: Our results suggest that miR-191 down-regulation plays a role in thyroid neoplasias of the follicular histotype, likely by targeting CDK6

MiR-1 Is a Tumor Suppressor in Thyroid Carcinogenesis Targeting CCND2, CXCR4, and SDF-1 alpha

Context: Micro-RNA have emerged as an important class of short endogenous RNA that act as posttranscriptional regulators of gene expression and are constantly deregulated inhumancancer. MiR-1 has been found down-regulated in lung, colon, and prostate cancer. Objectives: In this study, we investigated the possible role of miR-1 in thyroid carcinogenesis. Design: We have analyzed miR-1 expression in a panel of thyroid neoplasias including benign and malignant lesions and searched for miR-1 targets. Results: Our results show that miR-1 expression is drastically down-regulated in thyroid adenomas and carcinomas in comparison with normal thyroid tissue. Interestingly, miR-1 down-regulation was also found in thyroid hyperproliferative nonneoplastic lesions such as goiters. We identified the CCND2, coding for the cyclin D2 (CCND2) protein that favors the G1/S transition, CXCR4, and SDF-1 alpha genes, coding for the receptor for the stromal cell derived factor-1 (SDF-1)/CXCL12 chemokine and its ligand SDF-1/CXCL12, respectively, as miR-1 targets. An inverse correlation was found between miR-1 expression and CXC chemokine receptor 4 (CXCR4) and SDF-1 alpha protein levels in papillary and anaplastic thyroid carcinomas. Consistent with a role of the CCND2 protein in cell proliferation and CXCR4 and SDF-1 alpha proteins in cell invasion and metastasis, functional studies demonstrate that miR-1 is able to inhibit thyroid carcinoma cell proliferation and migration. Conclusions: These results indicate the involvement of miR-1 in thyroid cell proliferation and migration, validating a role of miR-1 down-regulation in thyroid carcinogenesis. (J Clin Endocrinol Metab 96: E1388-E1398, 2011)Associazione Italiana per la Ricerca sul Cancr

CBX7 gene expression plays a negative role in adipocyte cell growth and differentiation

We have recently generated knockout mice for the Cbx7 gene, coding for a polycomb group protein that is downregulated in human malignant neoplasias. These mice develop liver and lung adenomas and carcinomas, which confirms a tumour suppressor role for CBX7. The CBX7 ability to downregulate CCNE1 expression likely accounts for the phenotype of the Cbx7-null mice. Unexpectedly, Cbx7-knockout mice had a higher fat tissue mass than wild-type, suggesting a role of CBX7 in adipogenesis. Consistently, we demonstrate that Cbx7-null mouse embryonic fibroblasts go towards adipocyte differentiation more efficiently than their wild-type counterparts, and this effect is Cbx7 dose-dependent. Similar results were obtained when Cbx7-null embryonic stem cells were induced to differentiate into adipocytes. Conversely, mouse embryonic fibroblasts and human adipose-derived stem cells overexpressing CBX7 show an opposite behaviour. These findings support a negative role of CBX7 in the control of adipocyte cell growth and differentiation

HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells

Glioblastoma multiforme (GBM) develops from a small subpopulation of stem-like cells, which are endowed with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. These cells are resistant to conventional chemo- and radiotherapy and are hence also responsible for tumor recurrence. HMGA1 overexpression has been shown to correlate with proliferation, invasion, and angiogenesis of GBMs and to affect self-renewal of cancer stem cells from colon cancer. The role of HMGA1 in GBM tumor stem cells is not completely understood