title: Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.
abstract: Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression.
authors.affiliation: Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors.forename: Younghye
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors.forename: Ju-Han
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea. Electronic address: apysk@korea.ac.kr.
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000367:Age Factors; D001271:Atlases as Topic; D051926:Basigin / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015894:Genome, Human; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000032:analysis*; D009124:Muscle Proteins / Q000032:analysis*; D009336:Necrosis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012307:Risk Factors; D027981:Symporters / Q000032:analysis*; D046888:Tissue Array Analysis; D047368:Tumor Burden; D015854:Up-Regulation; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D051926:Basigin; D014408:Biomarkers, Tumor; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C497886:BSG protein, human; C406962:SLC16A4 protein, human
keywords: Aerobic glycolysis; CD147; Monocarboxylate; Renal cell carcinoma; TCGA