Upregulation of YKL-40 Promotes Metastatic Phenotype and Correlates with Poor Prognosis and Therapy Response in Patients with Colorectal Cancer
Mariangela De Robertis,
Maria Raffaella Greco,
Rosa Angela Cardone,
Tommaso Mazza,
Flaviana Marzano,
Nikolay Mehterov,
Maria Kazakova,
Nikolay Belev,
Apollonia Tullo,
Graziano Pesole,
Victoria Sarafian,
Emanuela Signori
Affiliations
Mariangela De Robertis
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
Maria Raffaella Greco
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
Rosa Angela Cardone
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
Tommaso Mazza
Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
Flaviana Marzano
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy
Nikolay Mehterov
Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
Maria Kazakova
Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
Nikolay Belev
University Hospital Eurohospital, 4000 Plovdiv, Bulgaria
Apollonia Tullo
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy
Graziano Pesole
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
Victoria Sarafian
Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
Emanuela Signori
Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy
YKL-40 is a heparin- and chitin-binding glycoprotein that belongs to the family of glycosyl hydrolases but lacks enzymatic properties. It affects different (patho)physiological processes, including cancer. In different tumors, YKL-40 gene overexpression has been linked to higher cell proliferation, angiogenesis, and vasculogenic mimicry, migration, and invasion. Because, in colorectal cancer (CRC), the serological YKL-40 level may serve as a risk predictor and prognostic biomarker, we investigated the underlying mechanisms by which it may contribute to tumor progression and the clinical significance of its tissue expression in metastatic CRC. We demonstrated that high-YKL-40-expressing HCT116 and Caco2 cells showed increased motility, invasion, and proliferation. YKL-40 upregulation was associated with EMT signaling activation. In the AOM/DSS mouse model, as well as in tumors and sera from CRC patients, elevated YKL-40 levels correlated with high-grade tumors. In retrospective analyses of six independent cohorts of CRC patients, elevated YKL-40 expression correlated with shorter survival in patients with advanced CRC. Strikingly, high YKL-40 tissue levels showed a predictive value for a better response to cetuximab, even in patients with stage IV CRC and mutant KRAS, and worse sensitivity to oxaliplatin. Taken together, our findings establish that tissue YKL-40 overexpression enhances CRC metastatic potential, highlighting this gene as a novel prognostic candidate, a predictive biomarker for therapy response, and an attractive target for future therapy in CRC.
