DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma
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Nathaniel Weygant1, Dongfeng Qu1,2,3, Randal May1,2, Ryan M. Tierney1, William L. Berry4, Lichao Zhao5, Shweta Agarwal5, Parthasarathy Chandrakesan1, Harisha R. Chinthalapally1, Nicholas T. Murphy1, James D. Li1, Sripathi M. Sureban1,2,3, Michael J. Schlosser6, James J. Tomasek4 and Courtney W. Houchen1,2,3,6
1 Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK
2 Department of Veterans Affairs Medical Center, Oklahoma, OK
3 Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma, OK
4 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK
5 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK
6 COARE Biotechnology, Oklahoma, OK
Courtney W. Houchen, email:
Keywords: DCLK1, Renal Carcinoma, Tumor Stem Cell, Focal Adhesion, EMT
Received: October 31, 2014 Accepted: December 10, 2014 Published: December 11, 2014
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.
Ryan M. Tierney
William L. Berry
Harisha R. Chinthalapally
Nicholas T. Murphy
James D. Li
Sripathi M. Sureban
Michael J. Schlosser
James J. Tomasek
Courtney W. Houchen
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