Biomedical subjects

Milena S Nicoloso

Publications and source records attributed to Milena S Nicoloso.

4 recordsLinked to original sources

PubMed2006

Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer.

ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas and B-cell chronic lymphocytic leukemia. We found that, in the majority of ovarian carcinomas (61.5%) and in a significant proportion of ovarian and breast cancer cell lines (45%), ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After ARLTS1 restoration by adenoviral transduction, only the negative TOV-112 and the homozygously mutated (MUT) MCF7 cells, but not the OV-90 cells expressing a normal ARLTS1 product, underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the tumorigenic potential of TOV-112 in nude mice. On the contrary, the ARLTS1-MUT induced significantly lower levels of apoptosis in infected cells and reduced in vivo tumorigenesis only partially, supporting the hypothesis that Trp149Stop polymorphism is retained in the general population and predisposes to cancer because of a reduction, but not full loss, of normal ARLTS1 function.

ADP-Ribosylation Factors↗

PubMed2005

HMGA1 protein expression sensitizes cells to cisplatin-induced cell death.

HMGA1 proteins belong to a family of nonhistone chromatin proteins able to bind DNA in AT-rich regions and to interact with various transcription factors thus enhancing or inhibiting gene transcription by acting as architectural proteins. Although their expression is very low or absent in many adult tissues, HMGA1 proteins have been frequently found to be upregulated in human cancers and are expressed at high levels during embryogenesis, suggesting they could have a role in highly proliferating cells. We have previously demonstrated that HMGA1 expression in primary breast cancer and mammary carcinoma derived cell lines inversely correlated with BRCA1 expression and that HMGA1 is able to downregulate the expression of BRCA1 gene by binding directly to its promoter region. Being BRCA1 protein expression strictly linked to the DNA repair activity of the cell, we investigated whether HMGA1 expression was able to influence cellular responses to DNA damage. Here, we report that high expression levels of HMGA1 proteins in MCF-7 or mouse embryonic stem cells results in diminished BRCA1 expression and enhanced sensitivity to Cisplatin and Bleomycin. The increased DNA damage-induced cell death in HMGA1-expressing cells is likely due to a diminished cellular DNA repair activity. Therefore, we propose that high expression of HMGA1 protein in human malignant neoplasias, acting on BRCA1 expression, could contribute to the progression of malignant transformation influencing the response of the cells to the damaged DNA.

Animals↗

PubMed2005

p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion.

Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27(kip1) affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27(kip1) activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27(kip1) or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27(kip1) expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27(kip1) in different subcellular compartments.

Animals↗

PubMed2004

Linking inflammation to cell cycle progression.

Risk of gastrointestinal cancers is closely related to increased levels of oxidants in the balance between oxidant and anti-oxidant agents. A possible explanation of this epidemiological observation is the local loss of the epithelial barrier function with a focal inflammatory response. Accordingly, chronic inflammatory diseases represent well-known risk factors for cancer and, on the other hand, it is known that anti-inflammatory agents, demulcents and antioxidants markedly inhibit the development of colon cancer in animal models as well in humans. At molecular level a key role in the process that link inflammation to cellular transformation seems to be played by activation of Cyclooxygenase-2 (COX-2) together with production of Reactive Oxygen Intermediate (ROI). Both these events have been strictly linked with cell proliferation and transformation, although the intracellular pathways involved in these processes are still not completely understood. The uncontrolled proliferation, which is a landmark of cellular transformation, is accompanied by the deregulation of proteins involved in the control of cell cycle checkpoints. Altered expression and function of cyclooxygenase and nitric oxide synthase seem to influence, among others, the expression of proteins involved in the regulation of cell cycle progression. Similarly, anti-inflammatory and antioxidant agents may also act on the expression and function of several cell cycle regulating proteins. Understanding the mechanisms by which chronic inflammation contributes to genetic and epigenetic changes involved in the regulation of critical cell cycle checkpoints may help to develop more and more specific treatment strategies for reducing malignant transformation of these inflammatory diseases.

Animals↗