Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most frequently diagnosed cancers and the fourth leading cause of cancer-related death in the United States, suggesting that there is an urgent need to design novel strategies for achieving better treatment outcome of patients diagnosed with PDAC. Our previous study has shown that activation of Notch and NF-κB play a critical role in the development of PDAC in the compound K-Ras(G12D) and Ink4a/Arf deficient transgenic mice. However, the exact molecular mechanism by which mutated K-Ras and Ink4a/Arf deficiency contribute to progression of PDAC remains largely elusive. In the present study, we used multiple methods, such as real-time RT-PCR, Western blotting assay, and immunohistochemistry to gain further mechanistic insight. We found that the deletion of Ink4a/Arf in K-Ras(G12D) expressing mice led to high expression of PDGF-D signaling pathway in the tumor and tumor-derived cell line (RInk-1 cells). Furthermore, PDGF-D knock-down in RInk-1 cells resulted in the inhibition of pancreatosphere formation and down-regulation of EZH2, CD44, EpCAM, and vimentin. Moreover, we demonstrated that epithelial-mesenchymal transition (EMT) was induced in the compound mice, which is linked with aggressiveness of PDAC. In addition, we demonstrated that tumors from compound transgenic mice have higher expression of cancer stem cell (CSC) markers. These results suggest that the acquisition of EMT phenotype and induction of CSC characteristics could be linked with the aggressiveness of PDAC mediated in part through the activation of PDGF-D, signaling.
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.|Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui, P.R. China.
Zhiwei
Z
Wang
Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Shadan
S
Ali
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Sanjeev
S
Banerjee
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Bin
B
Bao
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Yiwei
Y
Li
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Asfar S
AS
Azmi
Department of Medicine, Indiana University, Indianapolis, Indiana.
Murray
M
Korc
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.|Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Fazlul H
FH
Sarkar
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D011905:Genes, ras; D006801:Humans; D008222:Lymphokines / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000172:deficiency / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008222:Lymphokines; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)