Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer.
Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer.
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DOI：
10.18632/oncotarget.19802
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发表时间：
2017-09-12
期刊：
影响因子：
--
通讯作者：
Ohtsuka M
中科院分区：
文献类型：
--
作者：
Suzuki K;Takano S;Yoshitomi H;Nishino H;Kagawa S;Shimizu H;Furukawa K;Miyazaki M;Ohtsuka M
胰腺导管腺癌（PDAC）具有高转移潜能。然而，在PDAC转移定植的机制仍然知之甚少。近年来，Metadherin（MTDH）已经作为几种癌症类型中的转移的关键介质出现，尽管MTDH在PDAC中的生物学作用尚未被研究。在这里，我们证明了MTDH在PDAC进展中的功能作用，特别是关注转移级联。体外研究表明，MTDH在转移性PDAC细胞中提供癌症干细胞（CSC）特性，并有助于PDAC细胞中具有上皮特征的失巢凋亡抗性。我们还进行了体内研究，使用原位移植和门静脉内注射作为肝转移的实验模型，以检查MTDH在转移部位的功能。MTDH敲低显著降低了两种实验小鼠模型中肝转移沿着上皮特征的发生率。总的来说，MTDH促进PDAC细胞中具有推定的CSC和上皮特性的转移性定殖。用TGF-β1瞬时处理PDAC细胞，以研究MTDH对上皮可塑性的作用。有趣的是，在转移性PDAC细胞的间质-上皮转化（MET）诱导过程中，MTDH表达与Twist 1表达呈负相关。这些结果表明，MTDH可能有助于MET诱导通过下调Twsit 1。最后，免疫组化表明MTDH过表达与PDAC患者的血行转移密切相关，并预测预后不良。这是MTDH在PDAC转移性定殖中的功能的首次证明。我们的数据表明MTDH靶向治疗可用于控制PDAC转移。
Pancreatic ductal adenocarcinoma (PDAC) has a high metastatic potential. However, the mechanism of metastatic colonization in PDAC remains poorly understood. Metadherin (MTDH) has emerged in recent years as a crucial mediator of metastasis in several cancer types, although the biological role of MTDH in PDAC has not been investigated. Here, we demonstrated the functional roles of MTDH in PDAC progression, especially focusing on the metastatic cascade. In vitro studies showed that MTDH provides cancer stem cell (CSC) properties in metastatic PDAC cells and contributes to anoikis resistance with epithelial characteristics in PDAC cells. We also performed in vivo studies using both orthotopic transplantation and intra-portal vein injection as experimental models of liver metastasis to examine the function of MTDH at the metastatic site. MTDH knockdown dramatically reduced the incidence of liver metastases along with epithelial features in both experimental mouse models. Collectively, MTDH facilitates metastatic colonization with putative CSC and epithelial properties in PDAC cells. PDAC cells were transiently treated with TGF-β1 to investigate the roles of MTDH on epithelial plasticity. Intriguingly, MTDH expression was negatively correlated with Twist1 expression during the Mesenchymal-Epithelial transition (MET) induction in metastatic PDAC cells. These results suggest that MTDH may contribute to MET induction via downregulation of Twsit1. Lastly, immunohistochemistry indicated that MTDH overexpression is closely associated with hematogenous metastasis and predicts poor prognosis in patients with PDAC. This is the first demonstration of MTDH function in PDAC metastatic colonization. Our data suggest that MTDH targeting therapy could be applied to control PDAC metastasis.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
星形胶质细胞升高基因 1 通过抑制转录因子 FOXO1 促进乳腺癌增殖
影响因子：
8
作者：
Li, J.;Yang, L.;Li, M.
通讯作者：
Li, M.
DOI：
10.1073/pnas.0912589107
发表时间：
2010-01-05
影响因子：
11.1
作者：
Rovira, Meritxell;Scott, Sherri-Gae;Leach, Steven D.
通讯作者：
Leach, Steven D.
影响因子：
1.2
作者：
Jeon, Hyun Yong;Choi, Murim;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
50.3
作者：
Wan L;Lu X;Yuan S;Wei Y;Guo F;Shen M;Yuan M;Chakrabarti R;Hua Y;Smith HA;Blanco MA;Chekmareva M;Wu H;Bronson RT;Haffty BG;Xing Y;Kang Y
通讯作者：
Kang Y