Assessment of MGP gene expression in cancer and contribution to prognosis.

Matrix Gla protein (MGP) was first identified as a calcification physiological inhibitor and the causal agent of the Keutel syndrome. MGP has been suggested to play a role in development, cell differentiation, and tumorigenesis. This study aimed to compare MGP expression and methylation status in different tumors and adjacent tissues, using The Cancer Genome Atlas (TCGA) data repository. We investigated if changes in MGP mRNA expression were correlated to cancer progression and whether the correlation coefficients could be used for prognosis. Strong correlations were observed between altered MGP levels and disease progression in breast, kidney, liver, and thyroid cancers, suggesting that it could be used to complement current clinical biomarker assays, for early cancer diagnosis. We have also analyzed MGP methylation and identified CpG sites in its promoter and first intron with clear differences in methylation status between healthy and tumoral tissue providing evidence for epigenetic regulation of MGP transcription. Furthermore, we demonstrate that these alterations correlate with the overall survival of the patients suggesting that its assessment can serve as an independent prognostic indicator of patients' survival.

Data on the evaluation of FGF2 gene expression in Colorectal Cancer.

The data presented in this article is related with the research paper entitled "Evaluation of MGP gene expression in colorectal cancer", available on Gene journal [1]. From all the transcription factors known to regulate MGP, FGF2 is the most described in colon adenocarcinoma and colon tumor cell lines, where it was shown to: i) contribute for the invasiveness potential; and ii) promote proliferation and survival of colorectal cancer cells. These in vitro studies pose the hypothesis that FGF2 associated signaling pathways could be promoting the regulation of others genes, such as MGP, that may lead to tumor progression which ultimately could result in poor prognosis in colon adenocarcinoma.

Evaluation of MGP gene expression in colorectal cancer.

PURPOSE: Matrix Gla protein (MGP) is a vitamin K-dependent, γ-carboxylated protein that was initially found to be a physiological inhibitor of ectopic calcifications affecting mainly cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for a human pathology, the Keutel syndrome, characterized by abnormal calcifications in cartilage, lungs, brain and vascular system. MGP was recently implicated in tumorigenic processes such as angiogenesis and shown to be abnormally regulated in several tumors, including cervical, ovarian, urogenital and breast. This fact has triggered our interest in analyzing the expression of MGP and of its regulator, the transcription factor runt related transcription factor 2 (RUNX2), in colorectal cancer (CRC). METHODS: MGP and RUNX2 expression were analyzed in cancer and non-tumor biopsies samples from 33 CRC patients and 9 healthy controls by RT-qPCR. Consequently, statistical analyses were performed to evaluate the clinical-pathological significance of MGP and RUNX2 in CRC. MGP protein was also detected by immunohistochemical analysis. RESULTS: Showed an overall overexpression of MGP in the tumor mucosa of patients at mRNA level when compared to adjacent normal mucosa and healthy control tissues. In addition, analysis of the expression of RUNX2 mRNA demonstrated an overexpression in CRC tissue samples and a positive correlation with MGP expression (Pearson correlation coefficient 0.636; p ≤ 0.01) in tumor mucosa. However correlations between MGP gene expression and clinical-pathological characteristics, such as gender, age and pathology classification did not provide relevant information that may shed light towards the differences of MGP expression observed between normal and malignant tissue. CONCLUSIONS: We were able to associate the high levels of MGP mRNA expression with a worse prognosis and survival rate lower than five years. These results contributed to improve our understanding of the molecular mechanism underlying MGP deregulation in cancer.

Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bone.

Paget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date PDB causing mutations were identified only in the Sequestosome 1 gene at the PDB3 locus. OPTN has been recently associated with PDB, however little is known about the effect of genetic variants in this gene in PDB pathophysiology. By sequencing OPTN in SQSTM1 non-carriers PDB patients we found 16 SNPs in regulatory, coding and non-coding regions. One of those was found to be associated with PDB in our cohort - rs2234968. Our results show that rs2238968 effect may be explained by a change in OPTN splicing that give rise to a predicted truncated protein. We also performed functional studies on the variants located in OPTN promoter - rs3829923 and the rare variant -9906 - to investigate putative regulators of OPTN. Our results show that OPTN expression seems to be regulated by SP1, RXR, E47, and the E2F family. In conclusion, our work suggests a potential pathophysiological role of SNPs in OPTN, giving a new perspective about the regulatory mechanisms of this gene. Ultimately we discovered a new variant associated with PDB in OPTN, reinforcing the relevance of this gene for the development of this bone disease.

Matrix Gla protein repression by miR-155 promotes oncogenic signals in breast cancer MCF-7 cells.

MGP is a protein that was initially associated with the inhibition of calcification in skeleton, soft tissues, and arteries, but more recently also implicated in cancer. In breast cancer, higher levels of MGP mRNA were associated with poor prognosis, but since this deregulation was never demonstrated at the protein level, we postulated the involvement of a post-transcriptional regulatory mechanism. In this work we show that MGP is significantly repressed by miR-155 in breast cancer MCF-7 cells, and concomitantly there is a stimulation of cell proliferation and cell invasiveness. This study brings new insights into the putative involvement of MGP and oncomiR-155 in breast cancer, and may contribute to develop new therapeutic strategies.