Lai Fo-Bao, Liu Wen-Ting, Jing Ying-Ying, Yu Guo-Feng, Han Zhi-Peng, Yang Xue, Zeng Jian-Xing, Zhang Hang-Jie, Shi Rong-Yu, Li Xiao-Yong, Pan Xiao-Rong, Li Rong, Zhao Qiu-Dong, Wu Meng-Chao, Zhang Ping, Liu Jing-Feng, Wei Li-Xin
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China; Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Cancer Lett. 2016 Aug 10;378(2):131-41. doi: 10.1016/j.canlet.2016.05.014. Epub 2016 May 18.
Due to the existence of cancer stem cells (CSCs), persistence and relapse of human hepatocellular carcinoma (HCC) are common after treatment with existing anti-cancer therapies. Emerging evidence indicates that lipopolysaccharide (LPS) plays a crucial role in aggravating HCC, but information about the effect of LPS on CSCs of HCC remains scant. Here, we report that the stemness of CD133(+) CSCs sorted from the human HCC cell line Huh7 was maintained well when cells were cultured with LPS. The reduction of CD133 expression was much lesser in cultured CSCs in the presence of LPS. In response to LPS stimulation, CSCs showed an increase in their activity of clonogenesis and tumorigenesis. LPS also supported maintaining CSC abilities of migration, invasion, and chemo-resistance. Treatment with HIF-1α-specific siRNA significantly reduced CD133 expression by CSCs at both mRNA and protein levels. Further, the expression of HIF-1α and CD133 was reduced in LPS-stimulated CSCs when the NF-κB inhibitor was added to the cell culture. HIF-1α-specific siRNA also effectively counteracted the effect of LPS on maintaining CSC abilities of migration and invasion. These data indicate that LPS, an important mediator in the liver tumor microenvironment, supports the maintenance of CSC stemness through signaling of the NF-κB/HIF-1α pathway. Our current study highlights LPS as a potential target for developing new therapeutic approaches to eliminate CSCs during the treatment of HCC.
由于癌症干细胞（CSCs）的存在，人类肝细胞癌（HCC）在现有抗癌疗法治疗后持续存在和复发很常见。新出现的证据表明，脂多糖（LPS）在加重肝癌方面起着关键作用，但关于LPS对肝癌CSCs影响的信息仍然很少。在这里，我们报告说，当用LPS培养细胞时，从人肝癌细胞系Huh7中分选出来的CD133(+) CSCs的干性得到了很好的维持。在存在LPS的情况下，培养的CSCs中CD133表达的降低要小得多。响应LPS刺激，CSCs的克隆形成和肿瘤发生活性增加。LPS还支持维持CSCs的迁移、侵袭和化疗抗性能力。用HIF-1α特异性siRNA处理在mRNA和蛋白质水平上均显著降低了CSCs的CD133表达。此外，当将NF-κB抑制剂添加到细胞培养物中时，LPS刺激的CSCs中HIF-1α和CD133的表达降低。HIF-1α特异性siRNA也有效地抵消了LPS对维持CSCs迁移和侵袭能力的影响。这些数据表明，LPS是肝肿瘤微环境中的一种重要介质，通过NF-κB/HIF-1α信号通路支持CSC干性的维持。我们目前的研究强调LPS作为开发新治疗方法以在肝癌治疗期间消除CSCs的潜在靶点。
