Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model.
OBJECTIVE
Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1(+/−) mice.


METHODS
Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.


RESULTS
Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.


CONCLUSIONS
Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.
From the Departments of *Medical Sciences, and †Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
Andreea
A
Barbu
Margareta Halin
MH
Lejonklou
Britt
B
Skogseid
D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005935:Glucagonoma / Q000235:genetics / Q000378:metabolism; D000077155:Granulins; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D018345:Mice, Knockout; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C484898:Men1 protein, mouse; D000077153:Progranulins; D011518:Proto-Oncogene Proteins