Oncotarget

Research Papers:

Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism

Sripathi M. Sureban, Mohammad F. Madhoun, Randal May, Dongfeng Qu, Naushad Ali, Javid Fazili, Nathaniel Weygant, Parthasarathy Chandrakesan, Kai Ding, Stanley A. Lightfoot, Courtney W. Houchen _

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Oncotarget. 2015; 6:37200-37215. https://doi.org/10.18632/oncotarget.5808

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Abstract

Sripathi M. Sureban1,4,5,*, Mohammad F. Madhoun1,4,*, Randal May1,4, Dongfeng Qu1,4,5, Naushad Ali1,4,5, Javid Fazili1,4, Nathaniel Weygant1, Parthasarathy Chandrakesan1,5, Kai Ding2, Stanley A. Lightfoot3, Courtney W. Houchen1,4,5,6

1Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

2Department of Biostatistics & Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

3Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

4Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA

5The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA

6COARE Biotechnology Inc., Oklahoma City, OK 73104, USA

*These authors have contributed equally to this work

Correspondence to:

Courtney W. Houchen, e-mail: courtney-houchen@ouhsc.edu

Sripathi M. Sureban, e-mail: sripathi-sureban@ouhsc.edu

Keywords: circulating DCLK1, biomarker, miRNA, cirrhosis, HCC

Received: September 16, 2015     Accepted: October 06, 2015     Published: October 16, 2015

ABSTRACT

Tumor stem cell marker Doublecortin-like kinase1 (DCLK1) is upregulated in several solid tumors. The role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. We immunostained tissues from human livers with HCC, cirrhosis controls (CC), and non-cirrhosis controls (NCC) for DCLK1. Western blot and ELISA analyses for DCLK1 were performed with stored plasma samples. We observed increased immunoreactive DCLK1 in epithelia and stroma in HCC and CCs compared with NCCs, and observed a marked increase in plasma DCLK1 from patients with HCC compared with CC and NCC. Analysis of the Cancer Genome Atlas’ HCC dataset revealed that DCLK1 is overexpressed in HCC tumors relative to adjacent normal tissues. High DCLK1-expressing cells had more epithelial-mesenchymal transition (EMT). Various tumor suppressor miRNAs were also downregulated in HCC tumors. We evaluated the effects of DCLK1 knockdown on Huh7.5-derived tumor xenograft growth. This was associated with growth arrest and a marked downregulation of cMYC, and EMT transcription factors ZEB1, ZEB2, SNAIL, and SLUG via let-7a and miR-200 miRNA-dependent mechanisms. Furthermore, upregulation of miR-143/145, a corresponding decrease in pluripotency factors OCT4, NANOG, KLF4, and LIN28, and a reduction of let-7a, miR-143/145, and miR-200-specific luciferase activity was observed. These findings suggest that the detection of elevated plasma DCLK1 may provide a cost-effective, less invasive tool for confirmation of clinical signs of cirrhosis, and a potential companion diagnostic marker for patients with cirrhosis and HCC. Our results support evaluating DCLK1 as a biomarker for detection and as a therapeutic target for eradicating HCC.

Author Information

Sripathi M. Sureban

Mohammad F. Madhoun

Randal May

Dongfeng Qu

Naushad Ali

Javid Fazili

Nathaniel Weygant

Parthasarathy Chandrakesan

Kai Ding

Stanley A. Lightfoot

Courtney W. Houchen
Primary Contact  _


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