Oncotarget

Research Papers:

Inflammatory and oncogenic roles of a tumor stem cell marker doublecortin-like kinase (DCLK1) in virus-induced chronic liver diseases

Naushad Ali, Parthasarathy Chandrakesan, Charles B. Nguyen, Sanam Husain, Allison F. Gillaspy, Mark Huycke, William L. Berry, Randal May, Dongfeng Qu, Nathaniel Weygant, Sripathi M. Sureban, Michael S. Bronze, Danny N. Dhanasekaran, Courtney W. Houchen _

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Oncotarget. 2015; 6:20327-20344. https://doi.org/10.18632/oncotarget.3972

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Abstract

Naushad Ali1,6,7, Parthasarathy Chandrakesan1, Charles B. Nguyen1, Sanam Husain4,6, Allison F. Gillaspy5,6, Mark Huycke2,6,7, William L. Berry3, Randal May1, Dongfeng Qu1, Nathaniel Weygant1, Sripathi M. Sureban1,6,7, Michael S. Bronze1, Danny N. Dhanasekaran3,6 and Courtney W. Houchen1,6,7,8

1 Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

2 Infectious Diseases, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

3 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

4 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

5 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

6 Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

7 Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

8 COARE Biotechnology, Oklahoma City, Oklahoma, OK, USA

Correspondence to:

Naushad Ali, email:

Courtney W. Houchen, email:

Keywords: DCLK1, HCV, cancer stem cell, inflammation, hepatocellular carcinoma

Received: April 04, 2015 Accepted: April 11, 2015 Published: April 29, 2015

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.

Author Information

Naushad Ali

Parthasarathy Chandrakesan

Charles B. Nguyen

Sanam Husain

Allison F. Gillaspy

Mark Huycke

William L. Berry

Randal May

Dongfeng Qu

Nathaniel Weygant

Sripathi M. Sureban

Michael S. Bronze

Danny N. Dhanasekaran

Courtney W. Houchen
Primary Contact  _


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