University of Oulu

Metzendorf, C.; Wineberger, K.; Rausch, J.; Cigliano, A.; Peters, K.; Sun, B.; Mennerich, D.; Kietzmann, T.; Calvisi, D.F.; Dombrowski, F.; Ribback, S. Transcriptomic and Proteomic Analysis of Clear Cell Foci (CCF) in the Human Non-Cirrhotic Liver Identifies Several Differentially Expressed Genes and Proteins with Functions in Cancer Cell Biology and Glycogen Metabolism. Molecules 2020, 25, 4141.

Transcriptomic and proteomic analysis of clear cell foci (CCF) in the human non-cirrhotic liver identifies several differentially expressed genes and proteins with functions in cancer cell biology and glycogen metabolism

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Author: Metzendorf, Christoph1; Wineberger, Katharina1; Rausch, Jenny1;
Organizations: 1Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany
2Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
3Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90570 Oulu, Finland
4Biocenter Oulu, University of Oulu, 90570 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.9 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2020
Publish Date: 2021-01-27


Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of Stbd1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have a significant effect on liver glycogen levels, indicating that additional factors are required for glycogen overload in CCF. Usp28 knockout mice did not show changes in glycogen storage in diethylnitrosamine-induced liver carcinoma, demonstrating that CCF are distinct from this type of cancer model, despite the decreased USP28 expression. Moreover, our data indicates that decreased USP28 expression is a novel factor contributing to the pre-neoplastic character of CCF. In summary, our work identifies several novel and unexpected candidates that are differentially expressed in CCF and that have functions in glycogen metabolism and tumorigenesis.

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Series: Molecules
ISSN: 1420-3049
ISSN-E: 1420-3049
ISSN-L: 1420-3049
Volume: 25
Issue: 18
Article number: 4141
DOI: 10.3390/molecules25184141
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This research was funded by grant RI2695/1-1 from the Deutsche Forschungsgemeinschaft (DFG).
Copyright information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (