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Parp‐1 genetic ablation in Ela–myc mice unveils novel roles for Parp‐1 in pancreatic cancer
Author(s) -
MartínezBosch Neus,
Iglesias Mar,
MunnéCollado Jessica,
MartínezCáceres Carlos,
Moreno Mireia,
Guerra Carmen,
Yélamos Jose,
Navarro Pilar
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4384
Subject(s) - pancreatic cancer , poly adp ribose polymerase , cancer research , parp inhibitor , biology , cancer , angiogenesis , apoptosis , polymerase , genetics , dna
Pancreatic cancer has a dismal prognosis and is currently the fourth leading cause of cancer‐related death in developed countries. The inhibition of poly( ADP ‐ribose) polymerase‐1 (Parp‐1), the major protein responsible for poly( ADP ‐ribosy)lation in response to DNA damage, has emerged as a promising treatment for several tumour types. Here we aimed to elucidate the involvement of Parp‐1 in pancreatic tumour progression. We assessed Parp‐1 protein expression in normal, preneoplastic and pancreatic tumour samples from humans and from K‐Ras‐ and c‐myc‐driven mouse models of pancreatic cancer. Parp‐1 was highly expressed in acinar cells in normal and cancer tissues. In contrast, ductal cells expressed very low or undetectable levels of this protein, both in a normal and in a tumour context. The Parp‐1 expression pattern was similar in human and mouse samples, thereby validating the use of animal models for further studies. To determine the in vivo effects of Parp‐1 depletion on pancreatic cancer progression, Ela–myc ‐driven pancreatic tumour development was analysed in a Parp‐1 knock‐out background. Loss of Parp‐1 resulted in increased tumour necrosis and decreased proliferation, apoptosis and angiogenesis. Interestingly, Ela–myc:Parp‐1 −/− mice displayed fewer ductal tumours than their Ela–myc:Parp‐1 +/+ counterparts, suggesting that Parp‐1 participates in promoting acinar‐to‐ductal metaplasia, a key event in pancreatic cancer initiation. Moreover, impaired macrophage recruitment can be responsible for the ADM blockade found in the Ela–myc:Parp‐1 −/− mice. Finally, molecular analysis revealed that Parp‐1 modulates ADM downstream of the Stat3– MMP7 axis and is also involved in transcriptional up‐regulation of the MDM2 , VEGFR1 and MMP28 cancer‐related genes. In conclusion, the expression pattern of Parp‐1 in normal and cancer tissue and the in vivo functional effects of Parp‐1 depletion point to a novel role for this protein in pancreatic carcinogenesis and shed light into the clinical use of Parp‐1 inhibitors. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd