2934

GSN

gelsolin;GSN;gelsolin

actin-depolymerizing factor|brevin

9q33

protein-coding

Cytoskeletal rearrangement occurs in variety of cellular processes and involves a wide spectrum of proteins. Gelsolin super family proteins control actin organization by severing and capping filament ends and nucleating actin assembly. Gelsolin is the founding member of this family and plays important role in pathogenesis of human neoplasia. This study aimed to investigate the germline mutations and expressional profile of Gelsolin in human breast cancer tissues. For germ line screening PCR-SSCP technique was used while expression was analyzed through quantitative real time PCR. Different types of mutations were observed in Gelsolin coding regions on exons 4, 10, 11, 14 and 15. These mutations include 3 missense nonsynonymous substitution mutations, 2 deletions, 1 insertion and 1 synonymous substitution mutation. Gelsolin transcript level was found significantly lower in breast tumor tissues compared to control samples (p=0.03). Low level of Gelsolin was found in metastatic patients (p=0.002) and patients who died from breast cancer (P=0.03) compared to disease free patients at final follow up. This study shows that level of Gelsolin is down regulated in breast cancer tissues and is linked with metastasis development and death in patients. It is concluded that genetic changes in coding regions of Gelsolin can potentially contribute to genetic instability. These genetic variations and expressional correlation with patient survival may prove to be of significant importance.

Gelsolin, one of a major actin-binding proteins, is involved in the regulation of actin cytoskeleton organization by its severing and capping activity towards actin filaments. Human colon adenocarcinoma cell line LS180 and its selected variants of different metastatic potential were used to check for a correlation between gelsolin level, its subcellular localization and the invasive capacity of cells. Based on immunoblotting experiments, a decreased level of gelsolin was detected in the most invasive 5W subline when compared to the parental cell line LS180. The intracellular distribution of actin filaments and gelsolin in colon adenocarcinoma cells was examined by confocal microscopy. In the 5W subline, unlike in the other examined cells, gelsolin was colocalized with filamentous actin at the cell periphery. In summary, in human colon adenocarcinoma cells, gelsolin level and its subcellular distribution seem to correlate with their metastatic potential.

Colorectal cancer (CRC) is one of the most common cancers worldwide. More than half of all CRC patients will develop metastases, which represents the major cause of death for CRC patients. CRC metastases confined in other organs are potentially resectable, and patients who receive curative resections appear to have better outcomes. Thus, the early detection of metastasis in CRC patients could improve their survival rate after curative surgery. Here, we report the use of Cy-dye labeling combined with multi-dimensional fractionation and mass spectrometry as a proteomics-based approach for identifying CRC metastasis-associated biomarker(s) in plasma samples collected from three CRC patients upon diagnosis of their primary and metastatic tumors. Among the eight identified proteins, we used Western blot analysis and an in-house-developed ELISA to validate the increased plasma levels of one, secretory (plasma) gelsolin, in >80% of CRC patients with distal metastases in a larger sample cohort (32 patients). We also found a significant increase of secretory gelsolin in plasma samples of stage IV versus stages I-III CRC patients before treatment. Furthermore, immunohistochemistry showed that secretory gelsolin was highly overexpressed in CRC tissue specimens compared to adjacent normal tissues, and a cell model study showed that secretory gelsolin may help regulate CRC cell migration.