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PLoS One. 2014 Jul 16;9(7):e101452. doi: 10.1371/journal.pone.0101452. eCollection 2014.

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

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
3
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
4
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
5
The Division of Hematology and Medical Oncology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
6
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

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 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.

PMID:
25029561
PMCID:
PMC4100754
DOI:
10.1371/journal.pone.0101452
[Indexed for MEDLINE]
Free PMC Article
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