Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.
Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.
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DOI：
10.1158/0008-5472.can-08-4312
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Wang Z;Li Y;Kong D;Banerjee S;Ahmad A;Azmi AS;Ali S;Abbruzzese JL;Gallick GE;Sarkar FH
尽管在许多方面取得了快速进展，但胰腺癌（PC）仍然是最难治疗的人类恶性肿瘤之一，部分原因是由于新发和获得性化疗和放射抗性。吉西他滨单药或与其他常规治疗药物联合使用是治疗晚期PC的标准治疗方法，对诊断患有这种致命疾病的患者的总生存期无任何显著改善。以往的研究表明，PC细胞是吉西他滨耐药（GR）获得上皮间质转化（EMT）表型，这是令人想起的“癌症干细胞样细胞（CSC）”，但导致EMT表型的分子机制尚未得到充分的研究。本研究表明，Notch-2及其配体Jagged-1在GR细胞中高度上调，这与Notch信号通路在EMT和CSC表型获得中的作用一致。我们还发现Notch信号的下调与GR细胞侵袭行为的降低有关。此外，通过siRNA方法下调Notch信号导致EMT表型部分逆转，导致间充质-上皮转化（MET），这与波形蛋白、ZEB 1、Slug、Snail和NF-κB的表达降低相关。这些结果提供了分子证据，表明Notch信号传导的激活与PC细胞的化学抗性表型（EMT表型）在机制上相关，表明通过新策略使Notch信号传导失活可能是克服化学抗性以预防肿瘤进展和/或治疗转移性PC的潜在靶向治疗方法。
Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat, in part due to de novo and acquired chemo- and radio-resistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype which is reminiscent of “cancer stem-like cells (CSC)”; however the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study demonstrates that Notch-2 and its ligand Jagged-1 are highly up-regulated in GR cells, which is consistent with the role of Notch signaling pathway in the acquisition of EMT and CSC phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition (MET), which was associated with decreased expression of vimentin, ZEB1, Slug, Snail and NF-κB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemo-resistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemo-resistance toward the prevention of tumor progression and/or treatment of metastatic PC.