Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition

• Published in: World journal of gastroenterology : WJG Vol. 15; no. 4; pp. 441 - 448
• Main Authors: Dong, Yu-Wei, Wang, Xing-Peng, Wu, Kai
• Format: Journal Article
• Language: English
• Published: United States Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University,Shanghai 200080, China%Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Yanchang Road (M),Shanghai 200072, China 28.01.2009; The WJG Press and Baishideng
• Subjects: Animals; Base Sequence; Cell Line, Tumor; Female; Humans; Mice; Mice, Nude; Neovascularization, Pathologic - prevention & control; Original; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PPAR gamma - metabolism; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Retinoid X Receptor alpha - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Rosiglitazone; Thiazolidinediones - pharmacology; Transplantation, Heterologous; Tretinoin - pharmacology; Vascular Endothelial Growth Factor A - genetics; 胰腺癌; 过氧化酶体; Angiogenesis; Peroxisome proliferator-activated receptor γ; Pancreatic carcinoma; Vascular endothelialgrowth factor
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.15.441

AIM： TO Study the possible actions and mechanisms or peroxisome proliferator-activated receptor γ （PPARγ）, a ligand-activated transcription factor, in pancreatic car- cinogenesis, especially in angiogenesis. METHODS： Expressions of PPARy and retinoid acid receptor （RXRα） were examined by reverse-transcription polymerase chain reaction （RT-PCR） with immunocyto- chemical staining. Pancreatic carcinoma cells, PANC-1, were treated either with 9-cis-RA, a ligand of RXRα, or with 15-deoxy-△12,14 prostaglandin J2 （15d-PGJ2）, a ligand of PPART, or both. Antiproliferative effect was evaluated by cell viability using methyltetrazolium （MTT） assay. A pancreatic carcinoma xenograft tumor model of nude mice was established by inoculating PANC-1 cells subcutaneously. Rosiglitazone, a specific ligand of PPARy, was administered via water drinking in experimental group of nude mice. After 75 d, all mice were sacrificed. Expression of proliferating cell nuclear antigen （PCNA） in tumor tissue was examined with immunohistochemical staining. Expression of vascular endothelial growth factor （VEGF） mRNA in PANC-1 cells, which were treated with 15d-PGJ2 or 9-cis-RA at various concentrations or different duration, was detected by semi-quantitative RT-PCR. Effects of Rosi- glitazone on changes of microvascular density （MVD） and VEGF expression were investigated in xenograft tumor tissue. Neovasculature was detected with immu- nohistochemistry staining labeled with anti-Ⅳ collagen antibody, and indicated by MVD. RESULTS： RT-PCR and immunocytochemical stain- ing showed that PPARγ and RXRα were expressed in PANC-1 cells at both transcription level and translation level. MTT assay demonstrated that 15d-PGJ2, 9-cis-RA and their combination inhibited the growth of PANC-1 cells in a dose-dependent manner. 9-cis-RA had a com- bined inhibiting action with 15d-PGJ2 on the growth of pancreatic carcinoma. In vivo studies revealed that Rosiglitazone significantly suppressed the growth of pancreatic carcinoma as compared to control group （0.48 ± 0.23 cm^3 vs 2.488 ± 0.59 cm^3, P 〈 0.05）, and the growth inhibition rate was 80.7%. Immuno- histochemistry study showed that PCNA was down regulated in Rosiglitazone-treated group compared to the control group. 15d-PGJ2, 9-cis-RA and their com- bination inhibited the expression of VEGF mRNA in PANC-1 cells in a dose- and time-dependent manner. MVD was decreased more significantly in Rosiglitazone- treated mice （10.67±3.07） than in the control group （31.44±6.06） （P 〈 0.01）. VEGF expression in xeno- graft tumor tissue was also markedly down-regulated in Rosiglitazone-treated mice. CONCLUSION： Activation of PPARγ, inhibits the growth of pancreatic carcinoma both in vitro and in vivo. Sup- pression of tumor angiogenesis by down-regulating the expression of VEGF may be one of the mechanisms by which PPARγ, activation inhibits the growth of pancre- atic carcinoma.