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Gut
2012 ; 61
(2
): 268-77
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Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth
by an Akt-dependent mechanism
#MMPMID22068162
Frampton G
; Invernizzi P
; Bernuzzi F
; Pae HY
; Quinn M
; Horvat D
; Galindo C
; Huang L
; McMillin M
; Cooper B
; Rimassa L
; DeMorrow S
Gut
2012[Feb]; 61
(2
): 268-77
PMID22068162
show ga
BACKGROUND AND OBJECTIVES: Cholangiocarcinoma is a devastating cancer of biliary
origin with limited treatment options. The growth factor, progranulin, is
overexpressed in a number of tumours. The study aims were to assess the
expression of progranulin in cholangiocarcinoma and to determine its effects on
tumour growth. METHODS: The expression and secretion of progranulin were
evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from
patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated
signalling in the expression of progranulin was assessed using a combination of
specific inhibitors and shRNA knockdown techniques. The effect of progranulin on
proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation
were assessed in vitro. Progranulin knockdown cell lines were established, and
the effects on cholangiocarcinoma growth were determined. RESULTS: Progranulin
expression and secretion were upregulated in cholangiocarcinoma cell lines and
tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBP?
pathway. Blocking any of these signalling molecules, by either pharmacological
inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin
expression. Treatment of cholangiocarcinoma cells with recombinant progranulin
increased cell proliferation in vitro by a mechanism involving Akt
phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1.
Knockdown of progranulin expression in cholangiocarcinoma cells decreased the
expression of proliferating cellular nuclear antigen, a marker of proliferative
capacity, and slowed tumour growth in vivo. CONCLUSIONS: Evidence is presented
for a role for progranulin as a novel growth factor regulating cholangiocarcinoma
growth. Specific targeting of progranulin may represent an alternative for the
development of therapeutic strategies.
|*Bile Ducts, Intrahepatic
[MESH]
|Animals
[MESH]
|Bile Duct Neoplasms/*metabolism/pathology
[MESH]
|Biomarkers, Tumor/*metabolism
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Proliferation
[MESH]
|Cholangiocarcinoma/*metabolism/pathology
[MESH]
|Forkhead Box Protein O1
[MESH]
|Forkhead Transcription Factors/metabolism
[MESH]
|Humans
[MESH]
|Immunoblotting
[MESH]
|Intercellular Signaling Peptides and Proteins/*metabolism
[MESH]
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