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


METHODS
Twenty 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.


RESULTS
Changes 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.


CONCLUSIONS
Right 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.
Servicio de Patología. Hospital Universitario de Araba, Álava, 01009, Spain. ivan_fernandez_vega@hotmail.com.
Iván
I
Fernández-Vega
Department of Morphology and Cell Biology, University of Oviedo, 33006, Oviedo, Spain. garciaolivia@uniovi.es.
Olivia
O
García-Suárez
University Institute of Oncology of Asturias, Oviedo, Spain. garciabeatriz@uniovi.es.|Department of Functional Biology, University of Oviedo, 33006, Oviedo, Spain. garciabeatriz@uniovi.es.
Beatriz
B
García
Department of Biotechnology, Neiker-Tecnalia Arkaute, 01080, Vitoria-Gasteiz, Spain. ainaracsu@gmail.com.
Ainara
A
Crespo
University Institute of Oncology of Asturias, Oviedo, Spain. astudillo@hca.es.|Department of Pathology, Hospital, Universitario Central de Asturias, 33006, Oviedo, Spain. astudillo@hca.es.
Aurora
A
Astudillo
University Institute of Oncology of Asturias, Oviedo, Spain. quirosluis@uniovi.es.|Department of Functional Biology, University of Oviedo, 33006, Oviedo, Spain. quirosluis@uniovi.es.
Luis M
LM
Quirós
D000368:Aged; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009362:Neoplasm Metastasis; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D019812:Heparan Sulfate Proteoglycans; D012334:RNA, Neoplasm