title: S100-A10, thioredoxin, and S100-A6 as biomarkers of papillary thyroid carcinoma with lymph node metastasis identified by MALDI imaging.
abstract: In papillary thyroid carcinoma (PTC), metastasis is a feature of an aggressive tumor phenotype. To identify protein biomarkers that distinguish patients with an aggressive tumor behavior, proteomic signatures in metastatic and non-metastatic tumors were investigated comparatively. In particular, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to analyze primary tumor samples. We investigated a tumor cohort of PTC (n = 118) that were matched for age, tumor stage, and gender. Proteomic screening by MALDI-IMS was performed for a discovery set (n = 29). Proteins related to the discriminating mass peaks were identified by 1D-gel electrophoresis followed by mass spectrometry. The candidate proteins were subsequently validated by immunohistochemistry (IHC) using a tissue microarray for an independent PTC validation set (n = 89). In this study, we found 36 mass-to-charge-ratio (m/z) species that specifically distinguished metastatic from non-metastatic tumors, among which m/z 11,608 was identified as thioredoxin, m/z 11,184 as S100-A10, and m/z 10,094 as S100-A6. Furthermore, using IHC on the validation set, we showed that the overexpression of these three proteins was highly associated with lymph node metastasis in PTC (p < 0.005). For functional analysis of the metastasis-specific proteins, we performed an Ingenuity Pathway Analysis and discovered a strong relationship of all candidates with the TGF-β-dependent EMT pathway. Our results demonstrated the potential application of the MALDI-IMS proteomic approach in identifying protein markers of metastasis in PTC. The novel protein markers identified in this study may be used for risk stratification regarding metastatic potential in PTC.
authors.affiliation: Department of Radiation Sciences, Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München-German Research Center for Environmental Health GmbH, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Nipp
authors.forename: Mareike
authors.initials: M
authors.lastname: Elsner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Balluff
authors.forename: Stephan
authors.initials: S
authors.lastname: Meding
authors.forename: Hakan
authors.initials: H
authors.lastname: Sarioglu
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Sandra
authors.initials: S
authors.lastname: Rauser
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma; D002291:Carcinoma, Papillary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D009418:S100 Proteins; D013879:Thioredoxins