KRAS/NF-κB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis

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 transcript...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-01, Vol.77 (1), p.100-111
Main Authors: Yuan, Peng, He, Xiao-Hong, Rong, Ye-Fei, Cao, Jing, Li, Yong, Hu, Yun-Ping, Liu, Yingbin, Li, Dangsheng, Lou, Wenhui, Liu, Mo-Fang
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Extracellular matrix
Gene Expression Regulation, Neoplastic - physiology
Heterografts
Humans
Inflammation
K-Ras protein
Matrilysin
Metastases
Metastasis
Mice
Mice, Inbred NOD
Mice, SCID
MicroRNAs - genetics
MicroRNAs - metabolism
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
NF-kappa B - genetics
NF-kappa B - metabolism
NF-κB protein
Pancreatic cancer
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Polymerase Chain Reaction
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
Signal Transduction - physiology
Transcriptome
Tumor suppressor genes
YY1 protein
YY1 Transcription Factor - genetics
YY1 Transcription Factor - metabolism
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-16-1898