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Evaluation of ATAD2 as a Potential Target in Hepatocellular Carcinoma

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Abstract

Purpose

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with lack of effective systemic chemotherapy. In this study, we aimed to evaluate the value of ATPase family AAA domain-containing protein 2 (ATAD2) as a biomarker and potential therapeutic target for HCC.

Methods

The expression of ATAD2 was tested in different HCC patient cohorts by immunohistochemistry and comparative transcriptional analysis. The co-expression of ATAD2 and proliferation markers was compared during liver regeneration and malignancy with different bioinformatics tools. The cellular effects of ATAD2 inactivation in liver malignancy was tested on cell cycle, apoptosis, and colony formation ability as well as tumor formation using RNA interference. The genes affected by ATAD2 inactivation in three different HCC cell lines were identified by global gene expression profiling and bioinformatics tools.

Results

ATAD2 overexpression is closely correlated with HCC tumor stage. There was gradual increase from dysplasia, well-differentiated and poorly-differentiated HCC, respectively. We also observed transient upregulation of ATAD2 expression during rat liver regeneration in parallel to changes in Ki-67 expression. ATAD2 knockdown resulted in apoptosis and decreased cell survival in vitro and decreased tumor formation in some HCC cell lines. However, three other HCC cell lines tested were not affected. Similarly, gene expression response to ATAD2 inactivation in different HCC cell lines was highly heterogeneous.

Conclusions

ATAD2 is a potential proliferation marker for liver regeneration and HCC. It may also serve as a therapeutic target despite heterogeneous response of malignant cells.

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Availability of Data and Material

The contributions for the study are included in the article/Online Resources. Raw microarray data that support the findings of this study and further information are available upon request from corresponding author.

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Acknowledgements

This work was part of PhD theses of H.Y. (Bilkent University, Ankara, Turkey). We would like to thank Izmir Biomedicine and Genome Center’s core facilities especially Optical Imaging and IBG Bioinformatics Platform (IBG-BIP) for their support during data collection and analysis.

Funding

This study was supported by the funds from TUBITAK (109S191, 111T558), Turkish Academy of Sciences, Dokuz Eylul University, and İzmir Biomedicine and Genome Center.

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Authors and Affiliations

  1. Izmir Biomedicine and Genome Center, Izmir, Turkey

    Umut Ekin, Cigdem Ozen, Peyda Korhan, Ezgi Bagirsakci, Hamdiye Uzuner, Hani Alotaibi, Nese Atabey, Gökhan Karakülah & Mehmet Ozturk

  2. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey

    Umut Ekin, Ezgi Bagirsakci, Hamdiye Uzuner, Hani Alotaibi & Gökhan Karakülah

  3. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

    Haluk Yuzugullu, Cigdem Ozen, Ozge Gursoy Yuzugullu & Mehmet Ozturk

  4. Institut Albert Bonniot, Grenoble, France

    Haluk Yuzugullu, Ozge Gursoy Yuzugullu & Mehmet Ozturk

  5. Department of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey

    Funda Yilmaz

  6. Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey

    Petek Ballar Kirmizibayrak

  7. Faculty of Medicine, Izmir Tinaztepe University, Izmir, Turkey

    Nese Atabey & Mehmet Ozturk

  8. Present Address: Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Bioinformatics group, Dresden, Germany

    Cigdem Ozen

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  1. Umut Ekin
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Contributions

Study conception and design: MO; experiments: UE, HY, CO, OY, PK, and EB. Bioinformatics and statistical analyses: GK, HU, and UE; evaluation of the data: MO, NA, HA, FY, and PBK; drafting of the manuscript: MO and UE. All authors were involved in finalization of the manuscript and approved the submitted version.

Corresponding author

Correspondence to Mehmet Ozturk.

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Ethics Approval

Study with clinical samples was approved by Ege University Ethics Committee. Animal experiments were approved by Bilkent University Animal Ethics Committee. (Decision No: 2006/1; Decision date: 10/5/2006).

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The authors declare no competing interests.

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Ekin, U., Yuzugullu, H., Ozen, C. et al. Evaluation of ATAD2 as a Potential Target in Hepatocellular Carcinoma. J Gastrointest Canc 52, 1356–1369 (2021). https://doi.org/10.1007/s12029-021-00732-9

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  • DOI: https://doi.org/10.1007/s12029-021-00732-9

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