Glypican-1 (GPC1)
protein in exosomes was recently identified as a
biomarker for the early detection of pancreatic ductal
adenocarcinoma (PDAC). Immunohistochemical analyses and in vitro assays were conducted to assess the usefulness of GPC1 as a PDAC
biomarker, to reveal the biological role of GPC1 in pancreatic
carcinogenesis, and to ascertain the regulation mechanism of GPC1. An aberrant overexpression of GPC1
protein which is usually absent in normal pancreatic duct, was a widespread marker across the full spectrum of human PDAC precursors, PDAC, and pancreatic cancerous stroma. In intraductal papillary-
mucinous neoplasms (IPMNs), GPC1 tended to be positive in gastric-type IPMN. KRAS mutations were found in all GPC1-positive IPMN cases and in one-third of GPC1-negative IPMN cases. In pancreatic cell lines, GPC1 depletion caused remarkable inhibition of cell growth and migration, suggesting its oncogenic roles. GPC1 depletion upregulated the molecules associated with cell cycle arrest in pancreatic cell lines. Furthermore, KRAS and ecotropic viral integration site 1 (EVI1)
oncoprotein upregulated GPC1 expression. In a clinical cohort, GPC1 overexpression was not correlated with
pancreatic cancer prognosis. Taken together, these findings suggest the necessity of establishing a threshold of GPC1 value for detecting pancreatic
malignancy because GPC1 is overexpressed even in low-grade PDAC precursors which do not always become malignant. Our study also reveals a new aspect of pancreatic
carcinogenesis: KRAS and EVI1, two important molecules in early phases of pancreatic
carcinogenesis, positively regulate GPC1 expression and likely promote pancreatic
carcinogenesis.