miR-155 is positively regulated by CBX7 in mouse embryonic fibroblasts and colon carcinomas, and targets the KRAS oncogene

Background: Loss of CBX7 expression has been described in several malignant neoplasias, including human colon and thyroid carcinomas proposing CBX7 as a tumor suppressor gene with a key role in cancer progression. This role is supported from the development of benign and malignant neoplasias in Cbx7 null mice. The aim of our work has been to investigate the mechanisms underlying the CBX7 oncosuppressor activity by analyzing the microRNAs (miRNAs) regulated by CBX7. Methods: The miRNA expression profiles of the mouse embryonic fibroblasts (MEFs) null for Cbx7 and the wild-type counterpart were analyzed by the miRNACHIP microarray and then validated by qRT-PCR. To asses KRAS as target of miR-155 we evaluated the protein levels after transfection of the synthetic miR-155. Human colon carcinoma samples have been investigated for the expression of CBX7 and miR-155. Results: Twenty miRNAs were found upregulated and nine, including miR-155, downregulated in cbx7-null MEFS in comparison with the wild-type ones. Then, we focused on miR-155 since several studies have shown its deregulated expression in several human malignancies and, moreover, was the most downregulated miRNA. Subsequently, we searched for miR-155 target genes demonstrating that KRAS protein levels are directly modulated by miR-155. A direct significant correlation (r = 0.6779) between CBX7 and miR-155 expression levels was found in a set of human colon carcinoma tissue samples. Conclusion: miR-155 is positively regulated by CBX7 in MEFs and colon carcinomas, and has KRAS as one of the target genes likely accounting for the anti-apoptotic activity ascribed to miR-155 in some tissue contexts

HMGA1-pseudogene overexpression contributes to cancer progression

Two pseudogenes for HMGA1, whose overexpression has a critical role in cancer progression, have been identified. They act as decoy for miRNAs that are able to target the HMGA1 gene then enhancing cell proliferation and migration. Moreover, these pseudogenes contain sequences that are potential target sites for cancer-related miRNAs. Interestingly, HMGA1 pseudogenes are highly expressed in human anaplastic thyroid carcinomas, that is one of the most aggressive tumor in mankind, but almost undetectable in well differentiated thyroid carcinomas

Polycomb protein family member CBX7 plays a critical role in cancer progression

Abstract: CBX7 is a polycomb protein that participates in the formation of polycomb repressive complex 1. Apart from few exceptions, CBX7 expression is lost in human malignant neoplasias and a clear correlation between its downregulated expression and a cancer aggressiveness and poor prognosis has been observed. These findings indicate a critical role of CBX7 in cancer progression. Consistently, CBX7 is able to differentially regulate crucial genes involved in cancer progression and in epithelial-mesenchymal transition, as osteopontin and E-cadherin. Recent evidences indicate a role of CBX7 also in the modulation of response to therapy. In conclusion, CBX7 represents an important prognostic factor, whose loss of expression in general indicates a bad prognosis and a progression towards a fully malignant phenotype

HMGA1-pseudogenes and cancer

Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer

Identification of a New Pathway for Tumor Progression: MicroRNA-181b Up-Regulation and CBX7 Down-Regulation by HMGA1 Protein

High mobility group A (HMGA) overexpression plays a critical role in neoplastic transformation. To investigate whether HMGA acts by regulating the expression of microRNAs, we analyzed the microRNA expression profile of human breast adenocarcinoma cells (MCF7) transfected with the HMGA1 gene, which results in a highly malignant phenotype. Among the microRNAs induced by HMGA1, we focused on miR-181b, which was overexpressed in several malignant neoplasias including breast carcinomas. We show that miR-181b regulates CBX7 protein levels, which are down-regulated in cancer, and promotes cell cycle progression. We also demonstrate that CBX7, being negatively regulated by HMGA, is able to negatively regulate miR-181b expression. Finally, there was a direct correlation between HMGA1 and miR-181b expression and an inverse correlation between HMGA1 and CBX7 expression in human breast carcinomas. These data indicate the presence of a novel pathway involving HMGA1, miR-181b, and CBX7, which leads to breast cancer progression

CBX7 Modulates the Expression of Genes Critical for Cancer Progression

<div><p>Background</p><p>We have previously shown that the expression of CBX7 is drastically decreased in several human carcinomas and that its expression progressively decreases with the appearance of a highly malignant phenotype. The aim of our study has been to investigate the mechanism by which the loss of CBX7 expression may contribute to the emergence of a more malignant phenotype.</p><p>Methods</p><p>We analyzed the gene expression profile of a thyroid carcinoma cell line after the restoration of CBX7 and, then, analyzed the transcriptional regulation of identified genes. Finally, we evaluated the expression of CBX7 and regulated genes in a panel of thyroid and lung carcinomas.</p><p>Results</p><p>We found that CBX7 negatively or positively regulates the expression of several genes (such as SPP1, SPINK1, STEAP1, and FOS, FOSB, EGR1, respectively) associated to cancer progression, by interacting with their promoter regions and modulating their transcriptional activity. Quantitative RT-PCR analyses in human thyroid and lung carcinoma tissues revealed a negative correlation between CBX7 and its down-regulated genes, while a positive correlation was observed with up-regulated genes.</p><p>Conclusion</p><p>In conclusion, the loss of CBX7 expression might play a critical role in advanced stages of carcinogenesis by deregulating the expression of specific effector genes.</p></div

CBX7 and CBX7-regulated gene expression levels are correlated in human carcinoma samples.

<p>We analyzed the expression of CBX7, FOS, FOSB, EGR1, SPP1, SPINK1 and STEAP1 by qRT-PCR in papillary thyroid carcinomas (PTC) (<b>A</b>) and human lung carcinoma samples (<b>B</b>). The expression of FOS, FOSB and EGR1 is down-regulated, as it occurs for CBX7, in the neoplastic tissues with respect to the normal counterparts. Conversely, the expression of SPP1, SPINK1 and STEAP1 was up-regulated in the neoplastic samples with respect to the normal tissues, showing an opposite tendency if compared with that of CBX7. Results are expressed as Fold Change (for PTC) or Relative Expression (for lung carcinomas) with respect to a pool of normal samples which were set equal to 1. The range of variability of CBX7 and CBX7-regulated gene expression in normal thyroid and lung tissues was less than 10%.</p