Oncotarget

Research Papers:

HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity

Davide Valente, Gianluca Bossi, Alice Moncada, Mara Tornincasa, Stefania Indelicato, Salvatore Piscuoglio, Eva Diamantis Karamitopoulou, Armando Bartolazzi, Giovanna Maria Pierantoni, Alfredo Fusco, Silvia Soddu and Cinzia Rinaldo _

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Oncotarget. 2015; 6:10320-10334. https://doi.org/10.18632/oncotarget.3583

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Abstract

Davide Valente1, Gianluca Bossi1,2, Alice Moncada1,8, Mara Tornincasa3, Stefania Indelicato4, Salvatore Piscuoglio5,9, Eva Diamantis Karamitopoulou6, Armando Bartolazzi4, Giovanna Maria Pierantoni3, Alfredo Fusco3, Silvia Soddu1 and Cinzia Rinaldo1,7

1 Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy

2 Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy

3 Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy

4 Pathology Research Laboratory, Sant’Andrea University Hospital, Rome, Italy

5 Institute of Pathology, University Hospital of Basel, Basel, Switzerland

6 Translational Research, Institute of Pathology, University of Bern, Bern, Switzerland

7 Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), c/o Sapienza University, Rome, Italy

8 Present address: Institute of Medical Genetics, Catholic University, Rome, Italy

9 Present address: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA

Correspondence to:

Cinzia Rinaldo, email:

Keywords: HIPK2, cytokinesis failure, near-tetraploidy, CIN, tumorigenicity

Received: October 08, 2014 Accepted: February 13, 2015 Published: March 14, 2015

Abstract

HIPK2, a cell fate decision kinase inactivated in several human cancers, is thought to exert its oncosuppressing activity through its p53-dependent and -independent apoptotic function. However, a HIPK2 role in cell proliferation has also been described. In particular, HIPK2 is required to complete cytokinesis and impaired HIPK2 expression results in cytokinesis failure and tetraploidization. Since tetraploidy may yield to aneuploidy and chromosomal instability (CIN), we asked whether unscheduled tetraploidy caused by loss of HIPK2 might contribute to tumorigenicity. Here, we show that, compared to Hipk2+/+ mouse embryo fibroblasts (MEFs), hipk2-null MEFs accumulate subtetraploid karyotypes and develop CIN. Accumulation of these defects inhibits proliferation and spontaneous immortalization of primary MEFs whereas increases tumorigenicity when MEFs are transformed by E1A and Harvey-Ras oncogenes. Upon mouse injection, E1A/Ras-transformed hipk2-null MEFs generate tumors with genetic alterations resembling those of human cancers derived by initial tetraploidization events, such as pancreatic adenocarcinoma. Thus, we evaluated HIPK2 expression in different stages of pancreatic transformation. Importantly, we found a significant correlation among reduced HIPK2 expression, high grade of malignancy, and high nuclear size, a marker of increased ploidy. Overall, these results indicate that HIPK2 acts as a caretaker gene, whose inactivation increases tumorigenicity and causes CIN by cytokinesis failure.


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