Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) elicits prognoses that are among the worst of all cancers
Overexpression of ecotropic viral integration site 1 (EVI1) by pME18s plasmid transfection significantly upregulated the expression level of GPC1 mRNA in human pancreatic duct epithelial (HPDE) cell lines (Figure 2E). These results indicate that EVI1 might regulate GPC1 expression
We examined the relation between KRAS and GPC1 because GPC1 expression was partly correlated with KRAS status (Table 2) and because KRAS is extremely important in pancreatic precancerous lesions
Summary
Pancreatic ductal adenocarcinoma (PDAC) elicits prognoses that are among the worst of all cancers. At www.impactjournals.com/oncotarget the molecular level, activating mutations in KRAS are early and universal events. They are followed chronologically by inactivating mutations in CDKN2A, TP53, and SMAD4 [2]. This stepwise theory is supported by a genetic progression model of pancreatic carcinogenesis that gives rise to formation of an infiltrating cancer. Development of invasive pancreatic carcinoma occurs only after a long latency period. Detecting pancreatic precancerous (non-invasive) lesions during this latency period is necessary to improve the PDAC prognosis because early stage pancreatic cancers are associated with better survival [5]. The primary requisites verify the chronological change occurring in the early phase of pancreatic carcinogenesis and suggest a new modality including a valid tumor marker to treat this intractable disease
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