title: DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma.
abstract: Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC. Targeting these factors is key to increasing the survival of RCC patients. Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas' RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings.
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.|Department of Veterans Affairs Medical Center, Oklahoma, OK.|Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma, OK.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.|Department of Veterans Affairs Medical Center, Oklahoma, OK.
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Tierney
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Lichao
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Shweta
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Harisha R
authors.initials: HR
authors.lastname: Chinthalapally
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Murphy
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: James D
authors.initials: JD
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.|Department of Veterans Affairs Medical Center, Oklahoma, OK.|Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma, OK.
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.affiliation: COARE Biotechnology, Oklahoma, OK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schlosser
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Tomasek
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.|Department of Veterans Affairs Medical Center, Oklahoma, OK.|Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma, OK.|COARE Biotechnology, Oklahoma, OK.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D000089742:Doublecortin-Like Kinases; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D022001:Focal Adhesions / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases