Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character

Abstract

BackgroundHeparan sulfate proteoglycans (HSPGs) are complex molecules involved in the growth, invasion and metastatic properties of cancerous cells. This study analyses the alterations in the expression patterns of these molecules in right sided colorectal cancer (CRC), both metastatic and non-metastatic.MethodsTwenty right sided CRCs were studied. A transcriptomic approach was used, employing qPCR to analyze both the expression of the enzymes involved in heparan sulfate (HS) chains biosynthesis, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate (CS) chains, we include the study of the genes involved in the biosynthesis of these glycosaminoglycans. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences, of potential interest.ResultsChanges in proteoglycan core proteins differ depending on their location; those located intracellularly or in the extracellular matrix show very similar alteration patterns, while those located on the cell surface vary greatly depending on the nature of the tumor: glypicans 1, 3, 6 and betaglycan are affected in the non-metastatic tumors, whereas in the metastatic, only glypican-1 and syndecan-1 are modified, the latter showing opposing alterations in levels of RNA and of protein, suggesting post-transcriptional regulation in these tumors. Furthermore, in non-metastatic tumors, polymerization of glycosaminoglycan chains is modified, particularly affecting the synthesis of the tetrasaccharide linker and the initiation and elongation of CS chains, HS chains being less affected. Regarding the enzymes responsible for the modificaton of the HS chains, alterations were only found in non-metastatic tumors, affecting N-sulfation and the isoforms HS6ST1, HS3ST3B and HS3ST5. In contrast, synthesis of the CS chains suggests changes in epimerization and sulfation of the C4 and C2 in both types of tumor.ConclusionsRight sided CRCs show alterations in the expression of HSPGs, including the expression of the cell surface core proteins, many glycosiltransferases and some enzymes that modify the HS chains depending on the metastatic nature of the tumor, resulting more affected in non-metastatic ones. However, matrix proteoglycans and enzymes involved in CS fine structure synthesis are extensively modified independetly of the presence of lymph node metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1724-9) contains supplementary material, which is available to authorized users.

Elevated glypican‐1 expression is associated with an unfavorable prognosis in pancreatic ductal adenocarcinoma

“…Except for PDAC, the overexpression of GPC1 has been observed in the tumor tissues of gliomas, ameloblastomas, prostate cancer and esophageal squamous cell carcinoma (ESCC) . However, contradictory results were observed in colorectal cancer and breast cancer . In ESCC, high levels of GPC1 were also significantly associated with chemoresistance to cisplatin .…”

Glioma infiltration and extracellular matrix: key players and modulators

“…Neoplastic conditions allow for the modification of not only the expression levels or alternative gene splicing of proteoglycans but also their post‐translational modification (Datta, Pierce, & Datta, ; Iozzo & Cohen, ; Iozzo & Schaefer, ; Skandalis, Kletsas, Kyriakopoulou, Stavropoulos, & Theocharis, ). Particularly, the sulfation patterns of GAG chains in HS proteoglycans are dramatically altered (Fernández‐Vega et al, ; Lelongt et al, ; Muthana, Campbell, & Gildersleeve, ). The 6O‐sulfation, which is known to be critical for ligand interactions and activation of receptor tyrosine kinase (RTK) pathways, can be removed by extracellular sulfatases such as SULF1 and SULF2 (Lamanna, Frese, Balleininger, & Dierks, ; Wade et al, ).…”

Genome‐wide DNA methylation changes in transformed foci induced by nongenotoxic carcinogens

“…It has been reported that 70/88 breast cancer patients presented Usp38 expression at levels lower than that of the normal expression [Armakolas et al ]. Chst14, which transfers sulfate to the C‐4 hydroxyl of N‐acetylgalactosamine residues in dermatan sulfate, showed threefold deregulation in 80% of cases for both metastatic and nonmetastatic tumors [Fernández‐Vega et al ]. EZH2‐induced silencing of Vash1 by promoter methylation has been implicated in the progression and metastasis of several cancers [Lu et al ].…”