Abstract
BackgroundCholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line.MethodsProteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues.ResultsWe identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed.ConclusionsThis study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.
Highlights
Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis
The molecular mechanisms and genetic steps underlying the pathogenesis of this tumor remain largely unknown; the heterogeneity of these tumors, the different etiology and risk factors involved in tumor development, complicate the identification of suitable molecular target and treatment options
Large-scale technologies, such as whole genome sequencing, RNA-seq, microarray and methylation arrays, highlighted the real need to distinguish either the subtypes or the intra- and inter-tumoral heterogeneity of CCA [7,8,9]. It is well-known that some mutations such as IDH1, BAP1, ARID1A, and FGFR2 rearrangements are typically enriched in intrahepatic cholangiocarcinoma (ICC), while KRAS and TP53 in Extrahepatic cholangiocarcinoma (ECC) [10]
Summary
Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Large-scale technologies, such as whole genome sequencing, RNA-seq, microarray and methylation arrays, highlighted the real need to distinguish either the subtypes or the intra- and inter-tumoral heterogeneity of CCA [7,8,9]. It is well-known that some mutations such as IDH1, BAP1, ARID1A, and FGFR2 rearrangements are typically enriched in ICC, while KRAS and TP53 in ECC [10]. IDH1 and FGFR2 aberrations are associated with better prognosis, while KRAS and TP53 with worse outcome [11, 12] These data enforced the real need to treat ICC and ECC with tailored clinical approaches. Recent studies demonstrated that a classification based on etiology and molecular aspects, such as methylation and copy number variations, is complementary and more useful than the subtypes classification alone [14]
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