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Senescence in pancreatic carcinogenesis: from signalling to chromatin remodelling and epigenetics
  1. Shiv K Singh,
  2. Volker Ellenrieder
  1. Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University of Marburg, Marburg, Germany
  1. Correspondence to Dr Volker Ellenrieder, Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University of Marburg, Baldingerstrasse, Marburg 35043, Germany; ellenrie{at}med.uni-marburg.de

Abstract

Mutational activation of K-Ras is a key genetic event involved in the initiation of pancreatic carcinogenesis. However, K-Ras generally fails to transform precursor lesions into invasive cancers due to activation of powerful fail-safe programmes that counteract transformation and growth. The importance of cellular senescence, a permanent cell growth arrest, is increasingly being recognised as a critical fail-safe programme in pancreatic carcinogenesis. Emerging evidence suggests that oncogene-induced senescence requires transcriptional induction of the CDKN2A gene locus as well as comprehensive chromatin modifications involved in epigenetic silencing of pro-proliferative genes. Moreover, recent work in pancreatic cancer mouse models proposes that inactivation of the CDKN2A tumour suppressor locus is the molecular switch required for senescence evasion and unleashed K-Ras driven malignant transformation in the pancreas.

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