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 TreatmentReportar como inadecuado




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 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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 mechanisms 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.



Autor: Bin Bao, Shadan Ali, Aamir Ahmad, Asfar S. Azmi, Yiwei Li, Sanjeev Banerjee, Dejuan Kong, Seema Sethi, Amro Aboukameel, Subhash B

Fuente: http://plos.srce.hr/



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