title: Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.
abstract: Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM(+) AFP(+) hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not expressed in normal HpSCs. We performed a pair-wise comparison of the miRNA transcriptome of EpCAM(+) and corresponding EpCAM(-) cells isolated from two primary HCC specimens, as well as from two fetal livers and three healthy adult liver donors by small RNA deep sequencing. We found that miR-150, miR-155, and miR-223 were preferentially highly expressed in EpCAM(+) HCC cells, which was further validated. Their gene surrogates, identified using miRNA and messenger RNA profiling in a cohort of 292 HCC patients, were associated with patient prognosis. We further demonstrated that miR-155 was highly expressed in EpCAM(+) HCC cells, compared to corresponding EpCAM(-) HCC cells, fetal livers with enriched normal hepatic progenitors, and normal adult livers with enriched mature hepatocytes. Suppressing miR-155 resulted in a decreased EpCAM(+) fraction in HCC cells and reduced HCC cell colony formation, migration, and invasion in vitro. The reduced levels of identified miR-155 targets predicted the shortened overall survival and time to recurrence of HCC patients.
  
  
  CONCLUSIONS
  miR-155 is highly elevated in EpCAM(+) HCC cells and might serve as a molecular target to eradicate the EpCAM(+) CSC population in human HCCs.
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou, China.|University of Hawaii Cancer Center, Cancer Biology Program (Ji), Epidemiology Program (Zheng), Honolulu, HI.|Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.affiliation: University of Hawaii Cancer Center, Cancer Biology Program (Ji), Epidemiology Program (Zheng), Honolulu, HI.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Marshonna
authors.initials: M
authors.lastname: Forgues
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC.
authors.forename: Eliane L
authors.initials: EL
authors.lastname: Wauthier
authors.affiliation: Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC.
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wen
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Young
authors.initials: Y
authors.lastname: Song
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D012016:Reference Values; D015398:Signal Transduction; D015996:Survival Rate; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D035683:MicroRNAs