Original ContributionInflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma
Graphical abstract
Highlights
► In liver fluke-associated cholangiocarcinoma tissues, inflammation resulted in carbonylated proteins. ► Carbonylation of serotransferrin may be involved in iron accumulation in cholangiocarcinoma tissues. ► Carbonylation of serotransferrin, HSP70.1, and A1AT correlated with a poor prognosis.
Section snippets
Subjects
This study was approved by the Ethics Group of the Human Research Committee (HE480316) of Khon Kaen University, Thailand. CCA tissues were obtained with informed consent from patients who underwent surgical resections at Srinagarind Hospital, Khon Kaen University, between 2003 and 2008. Specimens from 36 cholangiocarcinoma patients (18 well differentiated, 4 moderately differentiated, and 1 poorly differentiated tubular adenocarcinoma cases and 13 papillary adenocarcinoma cases) were assessed
Identification of carbonylated proteins by 2D OxyBlot and MALDI–TOF/TOF MS
Fig. 1 shows the 2D-gel electrophoresis with CBB staining of total protein and 2D OxyBlot analysis of carbonylated protein isolated by the DNPH method for each pooled sample (whole (Fig. 1A) and magnified (Fig. 1B) images). 2D OxyBlot analysis detected about 40 carbonylated proteins. Carbonylation was greater in the tumor tissues than in nontumor and normal liver tissues. We performed additional analyses of six proteins of interest, as shown in Table 1, using immunoprecipitation for
Discussion
Our results indicate that carbonylated proteins were more highly accumulated in CCA tissues than in nontumor and normal liver tissues. Induction of an oxidant-generating system and reduction of an antioxidant system are well-recognized causes of oxidative stress. Oxidant-generating enzymes such as inducible nitric oxide synthase and cyclooxygenase 2 were found to be upregulated in animals with O. viverrini-induced CCA, in vitro cell lines, and clinical samples of CCA [22], [23], [24]. Moreover,
Conclusion
The carbonylation of serotransferrin, HSP70.1, and A1AT induced by inflammation may play critical roles in the carcinogenesis of CCA. Oxidative stress induced by inflammation causes the carbonylation of serotransferrin, leading to the accumulation and release of iron. The increased LIP may mediate Fenton reactions and generate ROS, which may contribute to all steps of CCA carcinogenesis. In addition, the carbonylation of HSP70.1 and A1AT may induce protein dysfunction and contribute to the
Acknowledgments
We thank the cadaver donors and their families as well as all of the CCA patients who donated specimens for this study. This work was partly supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grants 15406027, 19659150, and 22390121), the Khon Kaen University Research Fund (Grant 49-03-1-01-3), and the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (to R. Thanan and P. Yongvanit).
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2022, Clinica Chimica ActaCitation Excerpt :Goswami et al. discovered a relationship between oxidative stress and sialo-conjugates of prostate-specific antigen (PSA) and protein-bound sialic acid in malignant prostatic cancer [43]. Thanan et al. suggested that carbonylated TF-associated iron accumulation might cause oxidative stress through the Fenton reaction, resulting to CCA development [44]. However, the association between aberrant sialylation of transferrin and liver fluke infection leading to CCA progression should be investigated further to develop the diagnostic approach for CCA patients in our endemic region.
Extracellular acidification induces ROS- and mPTP-mediated death in HEK293 cells
2018, Redox BiologyCitation Excerpt :We speculate that the degree of pHe acidification, as well as its effect on pHc and other downstream effectors, might depend on the type of the cell, its metabolic state, and/or mode of ATP generation. Increased protein carbonylation is considered a marker of oxidative stress (e.g. [11,22]) and was observed in a large variety of human disorders including cardiac tissue following ischemia/reperfusion [48] and in cholangiocarcinoma during chronic inflammation [58]. Interestingly, extracellular acidification also was observed under these pathological conditions [54,56].
Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance
2017, Parasitology InternationalCitation Excerpt :Chronic inflammation caused by Ov infection leads to the overproduction and accumulation of reactive oxygen and reactive nitrogen radicals in inflamed target cells [6,40]. Moreover, increased levels of these radicals have the potential to damage DNA, proteins, lipids, and alter gene expression, all of which can contribute to cellular carcinogenesis [4,6–9]. Repeated cycles of cell damage and compensatory cell proliferation promote the development of tumor cells.
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2024, Antioxidants
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Present address: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.