Proteomic analysis identifies deregulated metabolic and oxidative-associated proteins in Italian intrahepatic cholangiocarcinoma patients

Abstract

Background 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. 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. Methods Proteome 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. Results We 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. Conclusions This 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.

Antioxidant Effect of Chrysanthemum morifolium (Chuju) Extract on H2O2-Treated L-O2 Cells as Revealed by LC/MS-Based Metabolic Profiling

“…Although citrulline was upregulated, ornithine, which is the precursor of citrulline, was downregulated by chrysanthemum extract. Previous work showed that aminoacylase-1 (3.5.1.14) was increased during oxidative stress, suggesting that chrysanthemum extract might inhibit the aminoacylase-1 and therefore cause the accumulation of N-acetylornithine and further decreases in ornithine [ 30 ]. Significantly, H 2 O 2 also decreased ornithine.…”

Acyl coenzyme A binding protein (ACBP): An aging‐ and disease‐relevant “autophagy checkpoint”

“…Immunohistochemical detection of ACBP/DBI also reveals high expression in cholangiocarcinoma (Cavalloni et al, 2021). ACBP/DBI mRNA levels are upregulated in non-small cell lung cancers (NSCLC), correlating with poor overall survival, cancer stage, and patient smoking history.…”

“…Mass‐spectrometric proteomics indicates that ACBP/DBI is highly abundant in colon adenocarcinoma compared to normal tissue (Atak et al, 2018 ). Immunohistochemical detection of ACBP/DBI also reveals high expression in cholangiocarcinoma (Cavalloni et al, 2021 ). ACBP/DBI mRNA levels are upregulated in non‐small cell lung cancers (NSCLC), correlating with poor overall survival, cancer stage, and patient smoking history.…”