The clinicopathological significance of monocarboxylate transporters in testicular germ cell tumors

// Eduardo C.A. Silva 1 , Flavio M. Carcano 2, 3 , Murilo Bonatelli 4 , Mauricio G. Zaia 4 , Filipa Morais-Santos 5, 6 , Fatima Baltazar 5, 6 , Luiz F. Lopes 3, 7 , Cristovam Scapulatempo-Neto 1, 4 and Celine Pinheiro 3, 4 1 Pathology Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil 2 Medical Oncology Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil 3 Barretos School of Health Sciences Dr. Paulo Prata – FACISB, Barretos, Sao Paulo, Brazil 4 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil 5 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal 6 ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimaraes, Portugal 7 Barretos Children's Cancer Hospital, Barretos, Sao Paulo, Brazil Correspondence to: Celine Pinheiro, email: celinepinheiro@gmail.com Keywords: testicular neoplasms; testicular germ cell tumors; monocarboxylate transporter; immunohistochemistry; Warburg effect Received: August 26, 2016      Accepted: February 26, 2018      Published: April 17, 2018 ABSTRACT Background: Metabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins. Results: MCT1, MCT4 and CD147 were associated with higher stages, higher M and N stages and histological type, while MCT4 was also associated with higher risk stratification, presence of vascular invasion, and lower overall and event free survival. MCT4 silencing in JEG-3 had no significant effect in cell viability, proliferation and death, as well as extracellular levels of glucose and lactate. However, MCT4-silenced cells showed an increase in migration and invasion. Conclusion: The proteins herein studied, with the exception of MCT2, were associated with characteristics of worse prognosis, lower global and event free survival of patients with GCTs. Also, in vitro MCT4 silencing stimulated cell migration and invasion. Materials and Methods: Immunohistochemical expression was evaluated on samples from 149 adult patients with testicular GCT, arranged in Tissue Microarrays (TMAs), and associated with the clinicopathological data. Also, MCT4 silencing studies using siRNA were performed in JEG-3 cells.