Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development.
Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.
Gironella
Meritxell
M
Institut National de Santé et de Recherche Médicale, U624 Stress Cellulaire, F-13288 Marseille, France.
Seux
Mylène
M
Xie
Min-Jue
MJ
Cano
Carla
C
Tomasini
Richard
R
Gommeaux
Julien
J
Garcia
Stephane
S
Nowak
Jonathan
J
Yeung
Man Lung
ML
Jeang
Kuan-Teh
KT
Chaix
Amandine
A
Fazli
Ladan
L
Motoo
Yoshiharu
Y
Wang
Qing
Q
Rocchi
Palma
P
Russo
Antonio
A
Gleave
Martin
M
Dagorn
Jean-Charles
JC
Iovanna
Juan L
JL
Carrier
Alice
A
Pébusque
Marie-Josèphe
MJ
Dusetti
Nelson J
NJ
D000818:Animals; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012334:RNA, Neoplasm / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; C495901:TP53 protein, human; C429767:TP53INP1 protein, human; D016159:Tumor Suppressor Protein p53; C518507:tumor protein 53-induced nuclear protein 1, mouse