title: STAT3 is necessary for proliferation and survival in colon cancer-initiating cells.
abstract: STAT3 is constitutively activated in colon cancer but its contributions in cancer-initiating cells have not been explored. In this study, we characterized STAT3 in aldehyde dehydrogenase (ALDH)-positive (ALDH(+)) and CD133-positive (CD133(+)) subpopulations of human colon tumor cells that exhibited more potent tumor-initiating ability than ALDH(-)/CD133(-) cells in tumor xenograft assays in mice. We found that ALDH(+)/CD133(+) cells expressed higher levels of the active phosphorylated form of STAT3 than either ALDH(-)/CD133(-) or unfractionated colon cancer cells. STAT3 inhibition by RNA interference-mediated knockdown or small-molecule inhibitors LLL12 or Stattic blocked downstream target gene expression, cell viability, and tumorsphere-forming capacity in cancer-initiating cells. Similarly, treatment of mouse tumor xenografts with STAT3 short hairpin RNA (shRNA), interleukin 6 shRNA, or LLL12 inhibited tumor growth. Our results establish that STAT3 is constitutively activated in colon cancer-initiating cells and that these cells are sensitive to STAT3 inhibition. These findings establish a powerful rationale to develop STAT3 inhibitory strategies for treating advanced colorectal cancers.
authors: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43205, USA. linlee75215@yahoo.com.cn
authors: Li
authors: L
authors: Lin
authors: Aiguo
authors: A
authors: Liu
authors: Zhengang
authors: Z
authors: Peng
authors: Huey-Jen
authors: HJ
authors: Lin
authors: Pui-Kai
authors: PK
authors: Li
authors: Chenglong
authors: C
authors: Li
authors: Jiayuh
authors: J
authors: Lin
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003499:Cyclic S-Oxides / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques / Q000379:methods; D006023:Glycoproteins / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050697:Retinal Dehydrogenase / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000071916:AC133 Antigen; D000880:Anthraquinones; D015703:Antigens, CD; D003499:Cyclic S-Oxides; D006023:Glycoproteins; C508600:IL6 protein, human; D015850:Interleukin-6; D007527:Isoenzymes; C549232:LLL12 compound; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; C517409:stattic; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase