Abstract
KRAS activation occurring in more than 90% of pancreatic ductal adenocarcinomas (PDAC) drives progression and metastasis, but the underlying mechanisms involved in these processes are still poorly understood. Here, we show how KRAS acts through inflammatory NF-κB signaling to activate the transcription factor YY1, which represses expression of the tumor suppressor gene miR-489. In PDAC cells, repression of miR-489 by KRAS signaling inhibited migration and metastasis by targeting the extracellular matrix factors ADAM9 and MMP7. miR-489 downregulation elevated levels of ADAM9 and MMP7, thereby enhancing the migration and metastasis of PDAC cells. Together, our results establish a pivotal mechanism of PDAC metastasis and suggest miR-489 as a candidate therapeutic target for their attack. Cancer Res; 77(1); 100-11. ©2016 AACR.
©2016 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / pathology*
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic / physiology*
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Heterografts
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Humans
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Mice
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Mice, Inbred NOD
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Mice, SCID
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / pathology
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Polymerase Chain Reaction
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Signal Transduction / physiology*
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Transcriptome
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YY1 Transcription Factor / genetics
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YY1 Transcription Factor / metabolism
Substances
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KRAS protein, human
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MIRN489 microRNA, human
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MicroRNAs
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NF-kappa B
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YY1 Transcription Factor
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YY1 protein, human
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Proto-Oncogene Proteins p21(ras)