Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma

被引:59
作者
Bhuria, Vikas [1 ]
Xing, Jun [1 ]
Scholta, Tim [1 ]
Khac Cuong Bui [1 ]
Mai Ly Thi Nguyen [1 ]
Malek, Nisar P. [1 ]
Bozko, Przemyslaw [1 ]
Plentz, Ruben R. [1 ,2 ]
机构
[1] Med Univ Hosp, Dept Internal Med 1, Otfried Muller Str 10, D-72076 Tubingen, Germany
[2] Bremen Nord Hosp, Dept Internal Med 2, Bremen, Germany
关键词
Cholangiocarcinoma; Hypoxia; Sonic Hedgehog pathway; Cancer stem cells; Epithelial to mesenchymal transition; Cyclopamine; INDUCIBLE FACTORS; CELLS; PATHWAY; ACTIVATION; RESISTANCE; EXPRESSION; INHIBITION; THERAPY; HIF-1-ALPHA; PROMOTES;
D O I
10.1016/j.yexcr.2019.111671
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Aberrant activation of Sonic Hedgehog (SHH) pathway has been implicated in a variety of cancers including cholangiocarcinoma (CC); however, the influencing factors are still unknown. Additionally, intratumoral hypoxia is known to contribute towards therapeutic resistance through modulatory effects on various pathways. In this study, we investigated the relationship between hypoxia and SHH pathway activation and the effect of this interplay on cancer sternness and epithelial-to- mesenchymal transition (EMT) during cholangiocarcinogenesis. Hypoxia promoted SHH pathway activation, evidenced by upregulated SHH and SMO levels, and enhanced glioma-associated oncogene homolog 1 (GLI1) nuclear translocation; whereas silencing of HIF-1 alpha impaired SHH upregulation. Hypoxia also enhanced the expression of cancer stem cell (CSC) transcription factors (NANOG, Oct4, SOX2), CD133 and EMT markers (N-cadherin, Vimentin), thereby supporting invasion. Cyclopamine treatment suppressed hypoxia induced SHH pathway activation, consequently reducing invasiveness by down-regulating the expression of CSC transcription factors, CD133 and EMT. Cyclopamine induced apoptosis in CC cells under hypoxia, suggesting that hypoxia induced activation of SHH pathway has modulatory effects on CC progression. Therefore, SHH signaling is proposed as a target for CC treatment, which is refractory to standard chemotherapy.
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页数:11
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