Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0030305 (
pancreatitis
)
16,014
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Kras
mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking,
pancreatitis
, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control
Pdx1
Cre
and
Pdx1
Cre
;LSL-
Kras
G12D
mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of
pancreatitis
, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the
Pdx1
Cre
;LSL-
Kras
G12D
mice but not in the control
Pdx1
Cre
mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in
Pdx1
Cre
;LSL-
Kras
G12D
mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the
Pdx1
Cre
;LSL-
Kras
G12D
mice, but its origin remained elusive due to leakiness of
Pdx1
Cre
in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors (
Epcam
,
Krt19
,
Prom1
,
Wt1
, and
Wwtr1
), stroma (
Dcn
,
Fn1
, and
Tn
c), and cytokines (
Tgfb1
and
Tnf
) and decreases expression of
Fgf21
and
Il6
in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of
nephronectin
, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC.
NEW & NOTEWORTHY
Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in
Pdx1
Cre
;LSL-
Kras
G12D
mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.
...
PMID:Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras. 3176 Jul 66
