title: Inflammatory and oncogenic roles of a tumor stem cell marker doublecortin-like kinase (DCLK1) in virus-induced chronic liver diseases.
abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. We previously showed that a tumor/cancer stem cell (CSC) marker, doublecortin-like kinase (DCLK1) positively regulates hepatitis C virus (HCV) replication, and promotes tumor growth in colon and pancreas. Here, we employed transcriptome analysis, RNA interference, tumor xenografts, patient's liver tissues and hepatospheroids to investigate DCLK1-regulated inflammation and tumorigenesis in the liver. Our studies unveiled novel DCLK1-controlled feed-forward signaling cascades involving calprotectin subunit S100A9 and NFκB activation as a driver of inflammation. Validation of transcriptome data suggests that DCLK1 co-expression with HCV induces BRM/SMARCA2 of SW1/SNF1 chromatin remodeling complexes. Frequently observed lymphoid aggregates including hepatic epithelial and stromal cells of internodular septa extensively express DCLK1 and S100A9. The DCLK1 overexpression also correlates with increased levels of S100A9, c-Myc, and BRM levels in HCV/HBV-positive patients with cirrhosis and HCC. DCLK1 silencing inhibits S100A9 expression and hepatoma cell migration. Normal human hepatocytes (NHH)-derived spheroids exhibit CSC properties. These results provide new insights into the molecular mechanism of the hepatitis B/C-virus induced liver inflammation and tumorigenesis via DCLK1-controlled networks. Thus, DCLK1 appears to be a novel therapeutic target for the treatment of inflammatory diseases and HCC.
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Naushad
authors.initials: N
authors.lastname: Ali
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Sanam
authors.initials: S
authors.lastname: Husain
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Allison F
authors.initials: AF
authors.lastname: Gillaspy
authors.affiliation: Infectious Diseases, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Huycke
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bronze
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors.forename: Danny N
authors.initials: DN
authors.lastname: Dhanasekaran
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.|COARE Biotechnology, Oklahoma City, Oklahoma, OK, USA.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000089742:Doublecortin-Like Kinases; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases
keywords: DCLK1; HCV; cancer stem cell; hepatocellular carcinoma; inflammation