Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2 (Retracted Article)
Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2 (Retracted Article)
复制标题
FOXO3a 的敲低通过 SPRY2 激活 β-catenin/TCF4 途径诱导上皮间质转化并促进胰腺导管腺癌的转移
DOI：
10.1186/s13046-019-1046-x
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发表时间：
2019-01-28
影响因子：
11.3
通讯作者：
Wang, Guoping
中科院分区：
文献类型：
--
作者：
Li, Jun;Yang, Rumeng;Wang, Guoping
早期侵袭和转移是导致胰腺导管腺癌（PDAC）预后不良的原因，而上皮间质转化（EMT）被认为是驱动肿瘤侵袭和转移的关键生物学进展。转录因子 FOXO3a 在各种类型的实体癌中失活，FOXO3a 的缺失与 EMT 和肿瘤转移相关。在本研究中，我们试图探讨受体酪氨酸激酶 (RTK) 信号传导的调节剂 SPRY2 是否参与 FOXO3a 介导的 EMT 和 PDAC 转移。在 130 对 PDAC 组织和癌旁胰腺组织中进行了免疫组织化学分析。通过细胞计数试剂盒和流式细胞术评估细胞增殖和凋亡，同时通过伤口愈合和transwell实验评估细胞迁移和侵袭。通过 qRT-PCR 和蛋白质印迹评估 mRNA 和蛋白质水平的变化。建立BALB/c裸鼠异种移植模型来评估体内肿瘤发生和转移。 PDAC组织中FOXO3a表达显着降低，并与PDAC患者转移相关的临床病理特征和不良预后相关。除了促进增殖和抑制细胞凋亡外，FOXO3a 或 SPRY2 的敲低还可诱导 EMT，并通过激活 β-catenin/TCF4 通路促进 PDAC 细胞的迁移和侵袭。此外，SPRY2的沉默逆转了FOXO3a过表达诱导的对EMT相关的PDAC细胞迁移和侵袭的抑制作用，而β-连环蛋白的阻断则逆转了SPRY2缺失的影响。 FOXO3a 敲低降低了 SPRY2 蛋白的稳定性，而 SPRY2 敲低则增强了 β-连环蛋白的稳定性。在体内，FOXO3a的敲低促进了PDAC细胞的致瘤能力和转移。我们的研究表明，FOXO3a的敲低通过SPRY2激活β-catenin/TCF4途径来诱导EMT并促进PDAC的转移。因此，FOXO3a 可能代表 PDAC 的候选治疗靶点。
Early invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. The transcription factor FOXO3a is inactivated in various types of solid cancers and the loss of FOXO3a is associated with EMT and tumor metastasis. In this study, we sought to explore whether SPRY2, a regulator of receptor tyrosine kinase (RTK) signaling, is involved in FOXO3a-mediated EMT and metastasis in PDAC.Immunohistochemistry was performed in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues. Cell proliferation and apoptosis were assessed by cell counting kit and flow cytometry, while cell migration and invasion were evaluated with wound healing and transwell assays. The changes in mRNA and protein levels were estimated by qRT-PCR and western blot. BALB/c nude mice xenograft model was established to evaluate tumorigenesis and metastasis in vivo.FOXO3a expression was remarkably reduced in PDAC tissues, and correlated with metastasis-associated clinicopathologic characteristics and poor prognosis in patients with PDAC. In addition to the promotion of proliferation and suppression of apoptosis, knockdown of FOXO3a or SPRY2 induced EMT and promoted the migration and invasion of PDAC cells via activation of the beta-catenin/TCF4 pathway. Moreover, silencing of SPRY2 reversed the suppressor effects induced by FOXO3a overexpression on EMT-associated migration and invasion of PDAC cells, while blockade of beta-catenin reversed the effects of SPRY2 loss. FOXO3a knockdown decreased SPRY2 protein stability, whereas SPRY2 knockdown enhanced beta-catenin protein stability. In vivo, FOXO3a knockdown promoted the tumorigenic ability and metastasis of PDAC cells.Our study suggests that knockdown of FOXO3a induces EMT and promotes metastasis of PDAC by activation of the beta-catenin/TCF4 pathway through SPRY2. Thus, FOXO3a may represent a candidate therapeutic target in PDAC.