Research Papers:

EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis

Mariko Tanaka, Shumpei Ishikawa, Tetsuo Ushiku, Teppei Morikawa, Takayuki Isagawa, Makoto Yamagishi, Hiroyuki Yamamoto, Hiroto Katoh, Kimiko Takeshita, Junichi Arita, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo and Masashi Fukayama _

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Oncotarget. 2017; 8:99552-99566. https://doi.org/10.18632/oncotarget.20601

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Mariko Tanaka1, Shumpei Ishikawa2, Tetsuo Ushiku1, Teppei Morikawa1, Takayuki Isagawa3, Makoto Yamagishi4, Hiroyuki Yamamoto5, Hiroto Katoh2, Kimiko Takeshita1, Junichi Arita6, Yoshihiro Sakamoto6, Kiyoshi Hasegawa6, Norihiro Kokudo7 and Masashi Fukayama1

1Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

2Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

3Department of Cardiovascular Medicine, Nagasaki University Hospital, Nagasaki, Japan

4Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Tokyo, Japan

5AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan

6Department of Hepatobiliary–pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

7National Center for Global Health and Medicine, Tokyo, Japan

Correspondence to:

Masashi Fukayama, email: [email protected]

Keywords: pancreatic cancer, Glypican-1, EVI1, KRAS

Received: December 15, 2016     Accepted: July 11, 2017     Published: September 01, 2017


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.

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