EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis

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.

[1]  R. Salgia,et al.  Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  A. Brandes,et al.  Contribution of microRNA analysis to characterisation of pancreatic lesions: a review , 2015, Journal of Clinical Pathology.

[3]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[4]  Yasuyuki Suzuki,et al.  Strategies for early detection of resectable pancreatic cancer. , 2014, World journal of gastroenterology.

[5]  J. Willmann,et al.  Stromal response to Hedgehog signaling restrains pancreatic cancer progression , 2014, Proceedings of the National Academy of Sciences.

[6]  S. Ishikawa,et al.  EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis , 2014, Oncogene.

[7]  J. Filmus,et al.  The role of glypicans in Hedgehog signaling. , 2014, Matrix biology : journal of the International Society for Matrix Biology.

[8]  S. Yachida,et al.  Evolution and dynamics of pancreatic cancer progression , 2013, Oncogene.

[9]  R. Gibbs,et al.  Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. , 2013, Gastroenterology.

[10]  A. Friedl,et al.  Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes , 2013, Molecular and Cellular Biology.

[11]  Nicole H. Wilson,et al.  Sonic Hedgehog Regulates Its Own Receptor on Postcrossing Commissural Axons in a Glypican1-Dependent Manner , 2013, Neuron.

[12]  Joseph T. Glessner,et al.  Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene. , 2013, Gastroenterology.

[13]  Lian Duan,et al.  GPC-1 may serve as a predictor of perineural invasion and a prognosticator of survival in pancreatic cancer. , 2017, Asian journal of surgery.

[14]  R. Hwang,et al.  Angiogenesis , Metastasis , and the Cellular Microenvironment Inhibition of the Hedgehog Pathway Targets the Tumor-Associated Stroma in Pancreatic Cancer , 2012 .

[15]  C. Heeschen,et al.  Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness , 2012, Cell cycle.

[16]  M. Korc,et al.  A KrasG12D-Driven Genetic Mouse Model of Pancreatic Cancer Requires Glypican-1 for Efficient Proliferation and Angiogenesis , 2011, Oncogene.

[17]  S. Ishikawa,et al.  Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis , 2011, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[18]  Kohei Miyazono,et al.  Emerging complexity of microRNA generation cascades. , 2011, Journal of biochemistry.

[19]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[20]  M. Hebrok,et al.  KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma , 2010, Nature Reviews Cancer.

[21]  Jia Yu,et al.  miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. , 2010, Cancer research.

[22]  Hiroshi I. Suzuki,et al.  Dynamics of microRNA biogenesis: crosstalk between p53 network and microRNA processing pathway , 2010, Journal of Molecular Medicine.

[23]  M. Goto,et al.  Significance of mucin expression in pancreatobiliary neoplasms , 2010, Journal of hepato-biliary-pancreatic sciences.

[24]  J. L. Goodman,et al.  Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia , 2008, Proceedings of the National Academy of Sciences.

[25]  Jason Gunn,et al.  Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. , 2008, The Journal of clinical investigation.

[26]  H. Friess,et al.  Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma. , 2006, International journal of oncology.

[27]  S. Salamat,et al.  Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells. , 2006, The American journal of pathology.

[28]  Michael Goggins,et al.  Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. , 2005, Cancer research.

[29]  H. Friess,et al.  Glypican-1 antisense transfection modulates TGF-beta-dependent signaling in Colo-357 pancreatic cancer cells. , 2004, Biochemical and biophysical research communications.

[30]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[31]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[32]  S. Crawley,et al.  Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas. , 2002, Gastroenterology.

[33]  J. Kleeff,et al.  Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. , 2001, Cancer research.

[34]  H. Friess,et al.  Stable transfection of a glypican-1 antisense construct decreases tumorigenicity in PANC-1 pancreatic carcinoma cells. , 1999, Pancreas.

[35]  H. Friess,et al.  The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. , 1998, The Journal of clinical investigation.

[36]  O. Dodge Tumours of the Pancreas , 1981, British Journal of Cancer.