Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells (Cancer Cell, 2010, 18:448-458)

報告日期: 2011/04/01
報告時間: 17:10/18:00
報告學生: 侯雅琴
講評老師: 劉校生

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0401-3.pdf

Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells
Kyoung Eun Lee1 and Dafna Bar-Sagi
Cancer cell, 2010,18:448-458
Date2011.04.01  PM17:10-18:00
PlaceRoom 602
Pancreatic ductal adenocarcinomas (PDAC) is the fourth leading cause of cancer-related death in the United States and carries a median survival of less than 6 months. In the initiation of PDAC, over 90% of activating KRas mutations are detected. The Ras protein is a representative example of the large family of GTPases that functions as molecular switches. Recent reports have shown that activation of oncogene Ras can induce senescence depending on the cellular context1. Cellular senescence serves as a tumor suppressive process and senescence bypass represents an important step in tumor development2. However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully clear.
To investigate the mechanisms of the senes­cence program, which linked to the oncogenic potential of mutated Ras in pancreatic ductal cells.
The authors used primary cells which were isolated from conditional KRasLSL-KrasG12Dknock-in mice to demonstrate the endogenous expression of KRas suppresses premature senescence in pancreatic duct epithelial cells (PDEC). They found that oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the transcription factor Twist, which in turn abrogates p16INK4A induction. Furthermore, the KRas-Twist-p16INK4A senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of PDEC.
The authors’ findings indicate that oncogenic KRas can contribute to pancreatic tumorigenesis and KRas-mediated senescence escape may be a potential target for therapeutic intervention.
1.         Sarkisian CJ et al. 2007. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol. 9,493-505
2.         A nsieau S et al. 2008. Induction of EMT by Twist proteins as a collateral effect of tumor- promoting inactivation of premature senescence. Cancer Cell. 14,79-89