title: Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
abstract: The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line.
  
  
  
  The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion, soft agar, and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses.
  
  
  
  The transformed cells exhibited enhanced proliferation, migration, and invasion, displayed anchorage-independent growth in soft agar, and grew orthotopic tumors with some histopathologic features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathologic features.
  
  
  
  The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Zhe
authors: Z
authors: Chang
authors: Zhongkui
authors: Z
authors: Li
authors: Xiaoyang
authors: X
authors: Wang
authors: Ya'an
authors: Y
authors: Kang
authors: Yuhui
authors: Y
authors: Yuan
authors: Jiangong
authors: J
authors: Niu
authors: Huamin
authors: H
authors: Wang
authors: Deyali
authors: D
authors: Chatterjee
authors: Jason B
authors: JB
authors: Fleming
authors: Min
authors: M
authors: Li
authors: James L
authors: JL
authors: Abbruzzese
authors: Paul J
authors: PJ
authors: Chiao
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D051379:Mice; D009154:Mutation; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000209:etiology*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018719:Erb-b2 Receptor Tyrosine Kinases; D051901:Smad4 Protein