【摘 要】
：
Over 90%of PDACs are associated with oncogenic KRAS mutations.Besides its well-established role in tumor initiation,oncogenic KRAS signaling is also required for the progression and metastasis of PDAC
【机 构】
：
Center for RNA Research,State Key Laboratory of Molecular Biology-University of Chinese Academy of S
【出 处】
：
中国生物化学与分子生物学会2016年全国学术会议
论文部分内容阅读
Over 90%of PDACs are associated with oncogenic KRAS mutations.Besides its well-established role in tumor initiation,oncogenic KRAS signaling is also required for the progression and metastasis of PDAC,but the underlying mechanism for these latter processes is still poorly understood.Here,we report for the first time that oncogenic KRAS in PDAC cells acts through inflammatory NF-κB signaling to activate YY1(Yin Yang 1),which encodes a transcriptional repressor of the MIR489 gene,and thereby reduce the level of miR-489.We demonstrate that this oncogenic KRAS-repressed miR-489 plays a decisive role in suppressing the migration and metastasis of PDAC cells by targeting two metalloproteinase genes,ADAM9 and MMP7.Downregulation of miR-489 by the oncogenic KRAS–NF-κB–YY1 regulatory axis leads to elevated levels of ADAM9 and MMP7,thus enhancing the migration and metastasis of PDAC cells.Together,our results reveal a novel mechanism of oncogenic KRAS-driven PDAC metastasis in which the NF-κB/YY1 regulatory axis downregulates miR-489 and in turn upregulates ADAM9 and MMP7 in PDAC cells,suggesting miR-489 as a promising therapeutic candidate to target PDAC metastasis.
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