title: SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells.
abstract: OBJECTIVE
  Some cancer cells have activities that are similar to those of stem cells from normal tissues, and cell dedifferentiation correlates with poor prognosis. Little is known about the mechanisms that regulate the stem cell-like features of cancer cells; we investigated genes associated with stem cell-like features of colorectal cancer (CRC) cells.
  
  
  METHODS
  We isolated colonospheres from primary CRC tissues and cell lines and characterized their gene expression patterns by microarray analysis. We also investigated the biological features of the colonosphere cells.
  
  
  RESULTS
  Expanded CRC colonospheres contained cells that expressed high levels of CD44 and CD166, which are markers of colon cancer stem cells, and had many features of cancer stem cells, including chemoresistance and radioresistance, the ability to initiate tumor formation, and activation of epithelial-mesenchymal transition (EMT). SNAIL, an activator of EMT, was expressed at high levels by CRC colonospheres. Overexpression of Snail in CRC cells induced most properties of colonospheres, including cell dedifferentiation. Two hundred twenty-seven SNAIL-activated genes were up-regulated in colonospheres; gene regulatory networks centered around interleukin (IL)-8 and JUN. Blocking IL-8 expression or activity disrupted SNAIL-induced stem cell-like features of colonospheres. We observed that SNAIL activated the expression of IL8 by direct binding to its E3/E4 E-boxes. In CRC tissues, SNAIL and IL-8 were coexpressed with the stem cell marker CD44 but not with CD133 or CD24.
  
  
  CONCLUSIONS
  In human CRC tissues, SNAIL regulates expression of IL-8 and other genes to induce cancer stem cell activities. Strategies that disrupt this pathway might be developed to block tumor formation by cancer stem cells.
authors.affiliation: Institution of Microbiology and Immunology, VGH-YM Genome Research Center, National Yang-Ming University, and Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hwang
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.forename: Ming-Long
authors.initials: ML
authors.lastname: Tsai
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Su
authors.forename: Shih-Ching
authors.initials: SC
authors.lastname: Chang
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Teng
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
authors.forename: Yuan-Tzu
authors.initials: YT
authors.lastname: Lan
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001665:Binding Sites; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D024721:E-Box Elements; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005326:Fetal Proteins / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D005472:Fluorouracil; D018960:Hyaluronan Receptors; D016209:Interleukin-8; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C497483:CD44 protein, human; C508606:CXCL8 protein, human