Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.
Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.
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DOI：
10.18632/oncotarget.5976
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发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
Lai MD
中科院分区：
文献类型：
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作者：
Chen WC;Chang YS;Hsu HP;Yen MC;Huang HL;Cho CY;Wang CY;Weng TY;Lai PT;Chen CS;Lin YJ;Lai MD
CD90被用作肝癌中癌症干细胞的标志物。我们旨在研究CD90促进肝癌进展的机制，并确定CD90信号通路上的新治疗靶点。CD90在肝癌细胞系中的异位表达增强了非贴壁生长和肿瘤进展。此外，CD90在体外促进了球体形成，并上调了癌症干细胞标志物CD133的表达。在肝癌标本中，CD45 - CD90⁺细胞中CD133的表达更高。天然致癌分子转化生长因子 - β - 1、肝细胞生长因子和乙肝表面抗原增加了CD90和CD133的表达。通过短发夹RNA（shRNA）或抗体抑制CD90可减弱CD133的诱导和非贴壁生长。慢病毒递送CD133 shRNA可消除由CD90诱导的致瘤性。CD90的异位表达诱导了哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化和腺苷酸活化蛋白激酶（AMPK）的去磷酸化。CD90中整合素结合 - RLD结构域的突变减弱了CD133的诱导和非贴壁生长。沉默β3整合素后观察到了类似结果。信号分析表明，AMPK/mTOR和β3整合素是CD90诱导CD133和肿瘤形成所必需的。重要的是，能量限制模拟剂OSU - CG5减少了新鲜肝肿瘤样本中CD90⁺细胞群，并抑制了肿瘤生长。相比之下，索拉非尼没有减少CD90⁺细胞群。总之，CD90 - 整合素 - mTOR/AMPK - CD133信号轴对促进肝癌发生至关重要。抑制该信号轴的分子，包括OSU - CG5和其他抑制剂，可能作为肝癌中潜在的新型癌症治疗靶点。
CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.