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

Zhe Chang, Huaiqiang Ju, Jianhua Ling, Zhuonan Zhuang, Zhongkui Li, Huamin Wang, Jason B. Fleming, James W Freeman, Dihua Yu, Peng Huang, Paul J. Chiao

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 TGFa 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.

Original languageEnglish (US)
Article numbere101452
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 16 2014

Fingerprint

Cyclin-Dependent Kinase Inhibitor p16
carcinogenesis
Carcinogenesis
Down-Regulation
Nestin
Cells
animal models
Neoplastic Cell Transformation
cells
p38 Mitogen-Activated Protein Kinases
mutants
Phosphatidylinositol 3-Kinases
Cell culture
Heterografts
human development
MAP Kinase Signaling System
phosphatidylinositol 3-kinase
Human Development
adenocarcinoma
mitogen-activated protein kinase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chang, Z., Ju, H., Ling, J., Zhuang, Z., Li, Z., Wang, H., ... Chiao, P. J. (2014). Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. PLoS One, 9(7), [e101452]. https://doi.org/10.1371/journal.pone.0101452

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

In: PLoS One, Vol. 9, No. 7, e101452, 16.07.2014.

Research output: Contribution to journalArticle

Chang, Z, Ju, H, Ling, J, Zhuang, Z, Li, Z, Wang, H, Fleming, JB, Freeman, JW, Yu, D, Huang, P & Chiao, PJ 2014, 'Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis', PLoS One, vol. 9, no. 7, e101452. https://doi.org/10.1371/journal.pone.0101452
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. / Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. In: PLoS One. 2014 ; Vol. 9, No. 7.
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