Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis.
Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in malignant lesions, but not in normal pancreatic tissues. To assess the role of Pim-3 in human pancreatic carcinogenesis in vivo and to determine the underlying Pim-3 signaling regulatory mechanisms, we established MiaPaca-2 cells overexpressing wild-type Pim-3 or Pim-3 kinase dead mutants (K69M-Pim-3) as well as PCI55 cells stably expressing Pim-3 shRNA or scrambled shRNA in a tetracycline-inducible manner. In addition, we conducted studies utilizing a nude mouse tumor xenograft model. Our results demonstrated that cells stably overexpressing wild-type Pim-3 exhibited functionally enhanced phosphorylation of Bad at Ser112 and increased proliferation. In contrast, the stable inactivation of Pim-3 by K69M-Pim-3 or silencing of Pim-3 expression by Pim-3 shRNA resulted in functionally decreased phosphorylation of Bad at Ser112 and higher apoptotic cells. Following subcutaneous injection of these stable cell lines, nude mice injected with Pim-3 overexpressing cells developed 100% subcutaneous tumors, together with increased PCNA-positive cells and enhanced intratumoral CD31-positive vascular areas. On the other hand, intratumoral neovascularization and tumor cell proliferation was attenuated in mice injected with Pim-3 kinase inactive cells, eventually reducing tumorigenicity in these mice to 46.6%. Moreover, Pim-3 overexpression upregulated the intratumoral levels of pSTAT3Try705, pSurvivinThr34, HGF, EGF, FGF-2 and VEGF, while the increases were markedly diminished on Pim-3 kinase inactivation. Collectively, the Pim-3 kinase emerges as being involved in accelerating human pancreatic cancer development and in promoting tumor neovascularization and subsequent tumor growth. Targeting Pim-3 may play a dual role in halting tumor progression, by promoting tumor cell death and blocking angiogenesis.
Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Bin
B
Liu
Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Zhen
Z
Wang
Department of Gastroenterology, Shenyang General Hospital, Shenyang, Liaoning, P.R. China.
Hong-Yu
HY
Li
Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Bo
B
Zhang
Department of Pathology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Bo
B
Ping
Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Ying-Yi
YY
Li
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases