E destruction [349]. Lately, improved expression of serglycin has been confirmed in nasopharyngeal and hepatocellular carcinoma. The elevated levels of serglycin in patients is correlated with unfavorable prognosis for general survival and recurrence in nasopharyngeal cancer and for illness no cost and distant metastasis absolutely free survival in HCC [350, 351]. Serglycin secreted from metastatic nasopharyngeal carcinoma cells promotes EMT, motility, invasion, and metastasis [351]. Non-glycanated core protein of serglycin fails to induce cancer cell motility suggesting the involvement of GAG chains in tumor promoting properties of serglycin.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptBiochim Biophys Acta. Author manuscript; accessible in PMC 2016 April 01.Theocharis et al.PageSerglycin is highly expressed in breast cancer tissues and cell lines [33]. The mRNA levels of serglycin are markedly up-regulated in aggressive breast cancer cells clustered into Basal B subgroup, which exhibit an EMT gene signature and resemble breast cancer stem cells being CD44highCD24low [33]. Basal-like breast cancers are correlated with elevated risk of metastatic spread and poor patient prognosis. In contrast, serglycin is expressed in low levels in significantly less aggressive subtypes of breast cancer cells [33]. Biochemical characterization of proteoglycans secreted by aggressive MDA-MB-231 breast cancer cells GSK-3α manufacturer demonstrated that serglycin bearing CS chains is the key secreted proteoglycan and it is abundantly present inside the cytoplasm and cell membrane showing both filamentous and granular distribution [33]. Serglycin promotes breast cancer cell anchorage-independent growth, migration and invasion when it is over-expressed in minimally invasive MCF-7 breast cancer cells. Interestingly, over-expression of a mutant type of serglycin lacking GAG attachment sites fails to induce breast cancer cell aggressiveness demonstrating that distinct structure of CS-4S present on serglycin is very important for its functions in breast cancer [33]. CHST11 gene that particularly mediates 4-O sulfation of CS is highly expressed in MDA-MB-231 breast cancer cells advertising their binding to P-selectin by way of CS-4S chains and facilitating the formation of metastasis [352]. It is also of excellent significance that CS-4 chains regulates the functional properties of proteolytic enzymes like cathepsins, which are involved in ECM degradation and tumor metastases [8]. Serglycin also regulates immune HDAC1 web system by way of its ability to inhibit complement program activity. Serglycin isolated from myeloma and breast cancer cells inhibits the classical plus the lectin pathways of complement method by means of direct binding to C1q and MBL, respectively, and protects tumor cells from complement system attack [33, 353]. Only these CS-4S chains with a higher proportion of 4-sulfated disaccharides interact efficiently with complement proteins [353]. CS-E and in a lower extent heparin compete with CS-4 chains of serglycin for binding to C1q, whereas only CS-E competes for binding to MBL. Binding of serglycin to C1q or/and C1 inhibits the cleavage of C4 within the classical pathway. Within the lectin pathway, binding of serglycin to MBL either competes out MBL-associated proteases (MASPs) in the stalk region of MBL or sterically hinders cleavage of C2 and C4 by MASPs [353]. The inhibition of complement is often a terrific limitation through immunotherapy against several types of cancer. These findings suggest a part for serglycin.
