NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation.
NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation.
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DOI：
10.1155/2016/5272498
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发表时间：
2016
影响因子：
4.3
通讯作者：
Koenig A
中科院分区：
文献类型：
--
作者：
Hessmann E;Zhang JS;Chen NM;Hasselluhn M;Liou GY;Storz P;Ellenrieder V;Billadeau DD;Koenig A
腺泡向导管样表型的转分化是腺泡细胞对外部应激信号的决定性反应，被认为是胰腺癌发生的第一步。尽管胰腺癌（PDAC）的发展需要致癌的Kras，但致癌的Kras并不足以推动胰腺癌的发生超过恶性前病变的水平。相反，次要事件，如炎症诱导的表皮生长因子（EGFR）信号激活或诱导Sox9表达，是肿瘤形成所必需的。在此，我们旨在剖析在胰腺组织适应和PDAC起始的腺泡到导管化生过程中EGFR信号与Sox9基因表达之间的联系机制。我们发现炎症转录因子NFATc4是高度诱导的，并在细胞核中定位，以响应炎症诱导的EGFR信号。此外，我们证明NFATc4通过直接转录诱导Sox9驱动疫苗到导管的转化和PDAC的启动。因此，旨在破坏NFATc4诱导的策略可能有助于预防或治疗PDAC。
Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.