Abstract
Background/Aims: Incidence of cholangiocarcinoma is increasing worldwide, yet remaining highly aggressive and with poor prognosis. The mechanisms that drive cholangiocyte transition towards malignant phenotype are obscure. Cholangiocyte benign proliferation is subjected to a self-limiting mechanism based on the autocrine release of endogenous opioid peptides. Despite the presence of both, ligands interact with δ opioid receptor (OR), but not with μOR, with the consequent inhibition of cell growth. We aimed to verify whether cholangiocarcinoma growth is associated with failure of opioidergic regulation of growth control. Methods: We evaluated the effects of OR selective agonists on cholangiocarcinoma cell proliferation, migration and apoptosis. Intracellular signals were also characterised. Results: Activation of μOR, but not δOR, increases cholangiocarcinoma cell growth. Such an effect is mediated by ERK1/2, PI3K and Ca2+-CamKIIα cascades, but not by cAMP/PKA and PKCα. μOR activation also enhances cholangiocarcinoma cell migration and reduces death by apoptosis. The anti-apoptotic effect of μOR was PI3K dependent. Conclusions: Our data indicate that cholangiocarcinoma growth is associated with altered opioidergic regulation of cholangiocyte biology, thus opening new scenarios for future surveillance or early diagnostic strategies for cholangiocarcinoma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 523-533 |
| Number of pages | 11 |
| Journal | Digestive and Liver Disease |
| Volume | 41 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2009 |
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Keywords
- Cholangiocarcinoma
- Endogenous opioid peptides
- Proliferation
- Survival
ASJC Scopus subject areas
- Gastroenterology
- Hepatology
Cite this
Human cholangiocarcinoma development is associated with dysregulation of opioidergic modulation of cholangiocyte growth. / Marzioni, M.; Invernizzi, P.; Candelaresi, C.; Maggioni, M.; Saccomanno, S.; Selmi, C.; Rychlicki, C.; Agostinelli, L.; Cassani, B.; Miozzo, M.; Pasini, S.; Fava, G.; Alpini, G.; Benedetti, A.
In: Digestive and Liver Disease, Vol. 41, No. 7, 07.2009, p. 523-533.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human cholangiocarcinoma development is associated with dysregulation of opioidergic modulation of cholangiocyte growth
AU - Marzioni, M.
AU - Invernizzi, P.
AU - Candelaresi, C.
AU - Maggioni, M.
AU - Saccomanno, S.
AU - Selmi, C.
AU - Rychlicki, C.
AU - Agostinelli, L.
AU - Cassani, B.
AU - Miozzo, M.
AU - Pasini, S.
AU - Fava, G.
AU - Alpini, G.
AU - Benedetti, A.
PY - 2009/7
Y1 - 2009/7
N2 - Background/Aims: Incidence of cholangiocarcinoma is increasing worldwide, yet remaining highly aggressive and with poor prognosis. The mechanisms that drive cholangiocyte transition towards malignant phenotype are obscure. Cholangiocyte benign proliferation is subjected to a self-limiting mechanism based on the autocrine release of endogenous opioid peptides. Despite the presence of both, ligands interact with δ opioid receptor (OR), but not with μOR, with the consequent inhibition of cell growth. We aimed to verify whether cholangiocarcinoma growth is associated with failure of opioidergic regulation of growth control. Methods: We evaluated the effects of OR selective agonists on cholangiocarcinoma cell proliferation, migration and apoptosis. Intracellular signals were also characterised. Results: Activation of μOR, but not δOR, increases cholangiocarcinoma cell growth. Such an effect is mediated by ERK1/2, PI3K and Ca2+-CamKIIα cascades, but not by cAMP/PKA and PKCα. μOR activation also enhances cholangiocarcinoma cell migration and reduces death by apoptosis. The anti-apoptotic effect of μOR was PI3K dependent. Conclusions: Our data indicate that cholangiocarcinoma growth is associated with altered opioidergic regulation of cholangiocyte biology, thus opening new scenarios for future surveillance or early diagnostic strategies for cholangiocarcinoma.
AB - Background/Aims: Incidence of cholangiocarcinoma is increasing worldwide, yet remaining highly aggressive and with poor prognosis. The mechanisms that drive cholangiocyte transition towards malignant phenotype are obscure. Cholangiocyte benign proliferation is subjected to a self-limiting mechanism based on the autocrine release of endogenous opioid peptides. Despite the presence of both, ligands interact with δ opioid receptor (OR), but not with μOR, with the consequent inhibition of cell growth. We aimed to verify whether cholangiocarcinoma growth is associated with failure of opioidergic regulation of growth control. Methods: We evaluated the effects of OR selective agonists on cholangiocarcinoma cell proliferation, migration and apoptosis. Intracellular signals were also characterised. Results: Activation of μOR, but not δOR, increases cholangiocarcinoma cell growth. Such an effect is mediated by ERK1/2, PI3K and Ca2+-CamKIIα cascades, but not by cAMP/PKA and PKCα. μOR activation also enhances cholangiocarcinoma cell migration and reduces death by apoptosis. The anti-apoptotic effect of μOR was PI3K dependent. Conclusions: Our data indicate that cholangiocarcinoma growth is associated with altered opioidergic regulation of cholangiocyte biology, thus opening new scenarios for future surveillance or early diagnostic strategies for cholangiocarcinoma.
KW - Cholangiocarcinoma
KW - Endogenous opioid peptides
KW - Proliferation
KW - Survival
UR - http://www.scopus.com/inward/record.url?scp=67349261559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349261559&partnerID=8YFLogxK
U2 - 10.1016/j.dld.2008.09.011
DO - 10.1016/j.dld.2008.09.011
M3 - Article
C2 - 18948067
AN - SCOPUS:67349261559
VL - 41
SP - 523
EP - 533
JO - Digestive and Liver Disease
JF - Digestive and Liver Disease
SN - 1590-8658
IS - 7
ER -