title: ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133+/CD44+ liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133+/CD44+ cells had increased metastatic potential compared with non-CD133+/CD44+ cells. We also demonstrated that ELK3 expression was upregulated in CD133+/CD44+ cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133+/CD44+ LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1α (HIF-1α). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133+/CD44+ cells by regulating HIF-1α expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133+/CD44+ LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion.
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Eun Byul
authors.initials: EB
authors.lastname: Lee
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; C497483:CD44 protein, human; C527883:Elk3 protein, human; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors