title: Lipopolysaccharide supports maintaining the stemness of CD133(+) hepatoma cells through activation of the NF-κB/HIF-1α pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Fo-Bao
authors.initials: FB
authors.lastname: Lai
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liu
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Jing
authors.affiliation: Oncology Department, Ji'an Hospital, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Yu
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Han
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Zeng
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Hang-Jie
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Rong-Yu
authors.initials: RY
authors.lastname: Shi
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Li
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Pan
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Qiu-Dong
authors.initials: QD
authors.lastname: Zhao
authors.affiliation: Department of Comprehensive Treatment, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.affiliation: Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. Electronic address: drjingfeng@126.com.
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China. Electronic address: weilixin_smmu@163.com.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wei
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606023:PROM1 protein, human
keywords: Cancer stem cells; Lipopolysaccharide; Plasticity; Stemness maintenance; Tumor microenvironment