title: A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.
abstract: Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized. The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations. Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features. GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 α subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (P < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (P < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852-46.371, P = 0.007). MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.
authors.affiliation: From the Department of Surgery (JL, M-YS, CRL, S-WK, JJJ, K-HN, WYC); and the Department of Internal Medicine (SJ, CRK, DYS, EJL, YSJ), Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jandee
authors.initials: J
authors.lastname: Lee
authors.forename: Mi-Youn
authors.initials: MY
authors.lastname: Seol
authors.forename: Seonhyang
authors.initials: S
authors.lastname: Jeong
authors.forename: Cho Rok
authors.initials: CR
authors.lastname: Lee
authors.forename: Cheol Ryong
authors.initials: CR
authors.lastname: Ku
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Jong Ju
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Dong Yeob
authors.initials: DY
authors.lastname: Shin
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Nam
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.forename: Woong Youn
authors.initials: WY
authors.lastname: Chung
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D065150:Cellular Reprogramming; D016001:Confidence Intervals; D003430:Cross-Sectional Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D015999:Multivariate Analysis; D009333:Neck; D010085:Oxidative Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger; D056910:Republic of Korea; D012269:Ribosomal Proteins / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C584516:mitochondrial ribosomal protein L44, human