YKL-40/chitinase-3-like protein 1 is associated with poor prognosis and promotes cell growth and migration of cholangiocarcinoma
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YKL-40, a chitinase-like glycoprotein, is expressed at a high level in cancer patients. Its exact function is unknown and is the subject of current investigation. Here, we report the correlation of plasma YKL-40 levels with clinicopathological features of cholangiocarcinoma (CCA), a lethal bile duct cancer, particularly prevalent in Northeastern Thailand. Statistical analysis of plasma YKL-40 concentrations in 57 CCA patients and 41 normal healthy subjects gave a median value of 169.5 ng/mL for CCA patients compared with 46.9 ng/mL for the control subjects (P < 0.0001). There was no significant association of plasma YKL-40 levels with patient age, tumor grade, or histology type. However, Kaplan-Meier analysis suggested that the elevated plasma YKL-40 level was particularly associated with short survival in CCA patients (P = 0.038). Immunohistochemical examination of 34 CCA tissues revealed low expression of YKL-40 in CCA cells, but high expression in adjacent intratumoral stroma, liver, and connective tissues. Univariate analysis showed significant association of the intratumoral YKL-40 expression in CCA tissues with the non-papillary type CCA. Addition of rYKL-40 in the culture medium and transient expression of YKL-40 in CCA cell lines were shown to promote the growth and migration of the tumor cells, and that YKL-40 interacted with a cell-surface receptor involved in the Akt/Erk-mediated pathway. In conclusion, our results support the proposal of YKL-40 as a new candidate prognostic biomarker for cancer diseases.
KeywordsChitinase-3-like protein 1 Cholangiocarcinoma GH-18 glycosyl hydrolases Prognostic marker YKL-40
Phosphorylated (active) AKT/PKB (protein kinase B) kinase
Bovine serum albumin
Phosphorylated (active) extracellular signal-regulated kinase
Phosphate-buffered saline tween
Revolutions per minute
We thank the Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, for participating in collection of patient data and tumor samples. We would like to acknowledge Biochemistry Laboratory, the Center for Scientific and Technological Equipment, Suranaree University of Technology, for providing all research facilities. We greatly appreciate a critical proofreading of this manuscript by Dr. David Apps, Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, United Kingdom.
ST carried out all the experiments, performed data analysis, and prepared the manuscript draft. WC generated the human CHI3L1 construct. AS, SW, and BS provided patients’ plasma samples and paraffin-embedded tissues and clinical data related to the CCA patients. HC provided guidance on Transwell migration assay. WS was a grant holder, conceived the idea of research, provided advice on gene isolation, cloning, expression, and purification of rYKL-40, and revised and approved the manuscript. CT coordinated cancer studies, provided guidance on statistical analyses, immunohistochemistry, cell proliferation, and migration assays, and took part in manuscript preparation.
Compliance with ethical standards
Written informed consent was obtained from all patients. The study has been approved by the Ethics Committee for Human Research, Suranaree University of Technology (EC-55-17).
This work is financially supported by The Thailand Research Fund through the Royal Golden Jubilee (RGJ) Ph.D. Program (PHD/0054/2551) to ST and WS. WS and CS were also funded by Suranaree University of Technology (grant numbers SUT1-102-54-36-06 and SUT1-102-56-12-32).
Conflicts of interest
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