Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.
Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.
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DOI：
10.1371/journal.pone.0050165
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Bao B;Ali S;Ahmad A;Azmi AS;Li Y;Banerjee S;Kong D;Sethi S;Aboukameel A;Padhye SB;Sarkar FH
已知缺氧在细胞存活、血管生成、肿瘤侵袭和转移中起关键作用。低氧介导的低氧诱导因子（hypoxia-inducible factor，HIF）的过度表达与肿瘤的治疗耐药有关，并导致肿瘤患者预后不良。新出现的证据表明，缺氧和HIF途径有助于获得上皮-间充质转化（EMT），维持癌症干细胞（CSC）功能，并维持炎症的恶性循环-所有这些都导致治疗抗性。然而，缺氧/HIF驱动这些事件的精确分子机制尚未完全了解。在这里，我们首次表明，缺氧导致VEGF，IL-6和CSC签名基因Nanog，Oct 4和EZH 2的表达增加，与细胞迁移/侵袭和血管生成增加以及胰腺球的形成一致，同时伴随着人胰腺癌（PC）细胞中miR-21和miR-210表达增加。用CDF（一种新的合成化合物）处理PC细胞抑制VEGF和IL-6的产生，并下调Nanog、Oct 4、EZH 2 mRNA以及miR-21和miR-210在缺氧条件下的表达。CDF还导致细胞迁移/侵袭、血管生成和缺氧条件下胰球形成减少。此外，在人PC的小鼠原位模型中，CDF降低了体内miR-21、miR-210、IL-6、HIF-1α、VEGF和CSC特征的基因表达。总的来说，这些结果表明，CDF的抗肿瘤活性部分是通过肿瘤缺氧通路的失调介导的，因此CDF可能成为一种新的，有效的抗肿瘤剂PC治疗。
Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.
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影响因子：
10.5
作者：
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通讯作者：
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影响因子：
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Sarkar, Fazlul H.
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作者：
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37.3
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