Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis

• Published in: PloS one Vol. 9; no. 7; p. e101452
• Main Authors: Chang, Zhe, Ju, Huaiqiang, Ling, Jianhua, Zhuang, Zhuonan, Li, Zhongkui, Wang, Huamin, Fleming, Jason B, Freeman, James W, Yu, Dihua, Huang, Peng, Chiao, Paul J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16-07-2014; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; AKT protein; Animal models; Animals; Biology and Life Sciences; Cancer; Carcinogenesis; Carcinogenesis - genetics; Carcinogens; Cell culture; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cellular Senescence; Collaboration; Cyclin-Dependent Kinase Inhibitor p16 - deficiency; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-dependent kinase inhibitors; Deactivation; Disease; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, ras - genetics; Genetic transformation; Health aspects; Human papillomavirus; Humans; Inactivation; INK4 protein; Intermediate filament proteins; K-Ras protein; Kinases; Laboratories; MAP kinase; Medicine and Health Sciences; Metastases; Metastasis; Mice; Mutation; Neoplasm Metastasis; Nestin; Oncology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pathogenesis; Pathways; Senescence; Signal transduction; Signaling; Telomerase reverse transcriptase; Therapeutic applications; Transformation; Transformations (mathematics); Transforming growth factors; Tumorigenesis; Tumors; Xenografts; Xenotransplantation; United States > US; Texas; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101452

Activation of K-ras and inactivation of p16 are the most frequently identified genetic alterations in human pancreatic epithelial adenocarcinoma (PDAC). Mouse models engineered with mutant K-ras and deleted p16 recapitulate key pathological features of PDAC. However, a human cell culture transformation model that recapitulates the human pancreatic molecular carcinogenesis is lacking. In this study, we investigated the role of p16 in hTERT-immortalized human pancreatic epithelial nestin-expressing (HPNE) cells expressing mutant K-ras (K-rasG12V). We found that expression of p16 was induced by oncogenic K-ras in these HPNE cells and that silencing of this induced p16 expression resulted in tumorigenic transformation and development of metastatic PDAC in an orthotopic xenograft mouse model. Our results revealed that PI3K/Akt, ERK1/2 pathways and TGFα signaling were activated by K-ras and involved in the malignant transformation of human pancreatic cells. Also, p38/MAPK pathway was involved in p16 up-regulation. Thus, our findings establish an experimental cell-based model for dissecting signaling pathways in the development of human PDAC. This model provides an important tool for studying the molecular basis of PDAC development and gaining insight into signaling mechanisms and potential new therapeutic targets for altered oncogenic signaling pathways in PDAC.