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Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

ABSTRACT: Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16(INK4A) induction. Moreover, the KRas-Twist-p16(INK4A) senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.

SUBMITTER: Lee KE

PROVIDER: S-EPMC3397918 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

Lee Kyoung Eun KE Bar-Sagi Dafna D

Cancer cell 20101101 5

Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription fact ...[more]

PMID: 21075310

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Project description:Background: Cellular senescence plays a critical role in the occurrence and development, and immune modulation of cancer. This research primarily investigated the role of senescence-associated genes (SAGs) in the survival and tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). Methods: From the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database, the gene expression profiles and clinical data of PDAC samples were downloaded. SAGs in the TCGA cohort were used to build a novel prognostic model and validated in the ICGC cohort. The relationship of signature with the immune landscape, tumor mutational burden (TMB), as well as the sensitivity of different therapies, was explored. Moreover, a nomogram was developed to predict the overall survival of PDAC patients. Results: A prognostic signature was constructed on basis of three SAGs, and patients in the low-risk score group had a longer survival time. The accuracy of the signature to distinguish different score groups was confirmed through principal component analysis (PCA) and the Receiver operator curves curve. The mRNA expression of the three signature genes was also verified in normal pancreatic and PDAC cell lines by RT-qPCR. The signature could independently predict the prognosis of PDAC patients and had broad applicability. Meanwhile, the nomogram predicted that 1- and 3-years survival rates were in good agreement with the observed overall survival rates. Low-risk patients had lower tumor mutational burden, and low-TMB patients had a better prognosis. Low- and high-risk patients exhibit distinct immune cell infiltration and immune checkpoint changes. By further analyzing the risk score, patients in the low-risk group were more responsive to immunotherapy and a variety of commonly used chemotherapeutic drugs. Conclusion: The prognostic signature can well predict the prognosis and assess the possibility of immunotherapy in personalized PDAC treatment.

Dataset Information

Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

Publications

Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

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