Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem-like Cells Marked by DCLK1 Kinase.
Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem-like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem-like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan-Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem-like cells in these malignancies. Cancer Res; 76(14); 4090-9. ©2016 AACR.
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma.
Nathaniel
N
Weygant
Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, Beijing, China.
Yang
Y
Ge
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma. United States Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. The Peggy and Charles Stephenson Cancer Center, Oklahoma City, Oklahoma.
Dongfeng
D
Qu
City of Hope National Medical Center, Duarte, California.
John S
JS
Kaddis
The University of Oklahoma Health Sciences Center Department of Cell Biology, Oklahoma City, Oklahoma.
William L
WL
Berry
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma. United States Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Randal
R
May
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma. United States Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. The Peggy and Charles Stephenson Cancer Center, Oklahoma City, Oklahoma.
Parthasarathy
P
Chandrakesan
COARE Biotechnology Inc., Oklahoma City, Oklahoma.
Edwin
E
Bannerman-Menson
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma. United States Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Kenneth J
KJ
Vega
The University of Oklahoma Health Sciences Center Department of Cell Biology, Oklahoma City, Oklahoma.
James J
JJ
Tomasek
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma.
Michael S
MS
Bronze
Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, Beijing, China. courtney-houchen@ouhsc.edu anguangyu@hotmail.com.
Guangyu
G
An
The University of Oklahoma Health Sciences Center Department of Medicine, Oklahoma City, Oklahoma. United States Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. The Peggy and Charles Stephenson Cancer Center, Oklahoma City, Oklahoma. COARE Biotechnology Inc., Oklahoma City, Oklahoma. courtney-houchen@ouhsc.edu anguangyu@hotmail.com.
Courtney W
CW
Houchen
D045744:Cell Line, Tumor; D000089742:Doublecortin-Like Kinases; D058750:Epithelial-Mesenchymal Transition; D005770:Gastrointestinal Neoplasms / Q000401:mortality* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis*; D035683:MicroRNAs / Q000032:analysis*; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis*
D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases