Premium
15‐PGDH inhibits cholangiocarcinogenesis through the induction of TAp63
Author(s) -
Lu Dongdong,
Han Chang,
Wu Tong
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.442.10
NAD+‐linked 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) is responsible for the catabolism of prostaglandins in a variety of cell types. In this study we showed that forced overexpression of 15‐PGDH in human cholangiocarcinoma cells (CCLP1) suppressed tumor cell growth, invasion and clonogenic formation capacity. In contrast, 15‐PGDH knockdown in CCLP1 cells enhanced tumor cell growth, invasion and clonogenic formation. Flow cytometry analysis revealed that 15‐PGDH overexpression induced cell cycle arrest at G1/S checkpoint. When implanted into SCID mice, 15‐PGDH overexpressed CCLP1 cells formed smaller xenograft tumors, whereas 15‐PGDH‐depleted cells formed larger xenograft tumors when compared with each of the corresponding controls (p<0.01). In addition, intratumoral injection of an adenoviral vector expressing 15‐PGDH (pAd‐15‐PGDH) significantly inhibited the growth of cholangiocarcinoima in SCID mice. Western blot analysis showed that 15‐PGDH induced the expression of TAp63, a key tumor suppressive gene. Furthermore, 15‐PGDH induced the phosphorylation of Smad2/3 and enhanced the interaction between p53 and pSmad2/3 in CCLP1 cells; the pSmad2/3 and p53 binding complex appeared to play a key role for the induction of TAp63 expression. Taken together, our data suggest that 15‐PGDH inhibits cholangiocarcinoma growth and this effect is at least in part through pSmad2/3 and p53‐mediated induction of TAp63.