Umut Ekin1,2, Haluk Yuzugullu3,4, Cigdem Ozen1,3,5, Peyda Korhan1, Ezgi Bagirsakci1,2, Funda Yilmaz6, Ozge Gursoy Yuzugullu3,4, Hamdiye Uzuner1,2, Hani Alotaibi1,2, Petek Ballar Kirmizibayrak7, Nese Atabey1,8, Gökhan Karakülah1,2, Mehmet Ozturk9,10,11,12. 1. Izmir Biomedicine and Genome Center, Izmir, Turkey. 2. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey. 3. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey. 4. Institut Albert Bonniot, Grenoble, France. 5. Present Address: Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Bioinformatics group, Dresden, Germany. 6. Department of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey. 7. Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey. 8. Faculty of Medicine, Izmir Tinaztepe University, Izmir, Turkey. 9. Izmir Biomedicine and Genome Center, Izmir, Turkey. mehmet.ozturk@ibg.edu.tr. 10. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey. mehmet.ozturk@ibg.edu.tr. 11. Institut Albert Bonniot, Grenoble, France. mehmet.ozturk@ibg.edu.tr. 12. Faculty of Medicine, Izmir Tinaztepe University, Izmir, Turkey. mehmet.ozturk@ibg.edu.tr.
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.
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.
Authors: Mary J Goldman; Brian Craft; Mim Hastie; Kristupas Repečka; Fran McDade; Akhil Kamath; Ayan Banerjee; Yunhai Luo; Dave Rogers; Angela N Brooks; Jingchun Zhu; David Haussler Journal: Nat Biotechnol Date: 2020-06 Impact factor: 54.908
Authors: C Caron; C Lestrat; S Marsal; E Escoffier; S Curtet; V Virolle; P Barbry; A Debernardi; C Brambilla; E Brambilla; S Rousseaux; S Khochbin Journal: Oncogene Date: 2010-06-28 Impact factor: 9.867
Authors: Marco Ciró; Elena Prosperini; Micaela Quarto; Ursula Grazini; Julian Walfridsson; Fraser McBlane; Paolo Nucifero; Giovanni Pacchiana; Maria Capra; Jesper Christensen; Kristian Helin Journal: Cancer Res Date: 2009-10-20 Impact factor: 12.701
Authors: Seong Joo Koo; Amaury E Fernández-Montalván; Volker Badock; Christopher J Ott; Simon J Holton; Oliver von Ahsen; Joern Toedling; Sarah Vittori; James E Bradner; Mátyás Gorjánácz Journal: Oncotarget Date: 2016-10-25