MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.
MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.
复制标题
MicroRNA-323-3p 通过直接抑制 SMAD2 和 SMAD3 抑制胰腺导管腺癌的细胞侵袭和转移。
DOI：
10.18632/oncotarget.7482
复制
发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Gou S
中科院分区：
文献类型：
--
作者：
Wang C;Liu P;Wu H;Cui P;Li Y;Liu Y;Liu Z;Gou S
胰腺导管腺癌（PDAC）占所有胰腺癌病例的96%，其特征在于快速进展、浸润和转移。转化生长因子-β（TGF-β）信号转导是肿瘤转移过程中的重要信号通路，而微小RNA（microRNA，miRNA）在肿瘤转移等多种生物学和病理学过程的调控中发挥着重要作用。然而，PDAC中miRNA调控和TGF-β信号激活的分子机制仍有待建立。本研究的结果表明，与正常胰腺组织和原代培养的胰腺导管上皮细胞中的水平相比，PDAC组织和细胞系中的miR-323- 3 p表达显著降低。进一步的研究表明，miR-323- 3 p直接靶向并抑制SMAD 2和SMAD 3，这两种成分都是TGF-β信号传导的关键成分。较低水平的miR-323- 3 p预测PDAC患者的预后较差。miR-323- 3 p的过表达可显著抑制PDAC细胞的体外迁移和侵袭能力，而miR-323- 3 p的沉默可增强PDAC细胞的体外迁移和侵袭能力。此外，使用体内小鼠模型，我们证明了miR-323- 3 p的过表达显著降低了PANC-1细胞的肺转移定植，而miR-323- 3 p的敲低增强了PANC-1细胞的肺转移定植。此外，miR-323- 3 p诱导的TGF-β信号传导抑制和细胞运动抑制部分地通过在PDAC细胞中过表达Smad 2和Smad 3来挽救。我们的研究结果表明，miR-323- 3 p的重新表达可能为PDAC患者的转移提供新的治疗靶点。
Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-β) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-β signaling in PDAC remain to be established. The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells. Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-β signaling. Lower levels of miR-323-3p predicted poorer prognosis in patients with PDAC. Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro. Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells. Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells. Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.