title: HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity.
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.
authors: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Davide
authors: D
authors: Valente
authors: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.|Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.
authors: Gianluca
authors: G
authors: Bossi
authors: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.|Present address: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors: Alice
authors: A
authors: Moncada
authors: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors: Mara
authors: M
authors: Tornincasa
authors: Pathology Research Laboratory, Sant'Andrea University Hospital, Rome, Italy.
authors: Stefania
authors: S
authors: Indelicato
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.|Present address: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors: Salvatore
authors: S
authors: Piscuoglio
authors: Translational Research, Institute of Pathology, University of Bern, Bern, Switzerland.
authors: Eva Diamantis
authors: ED
authors: Karamitopoulou
authors: Pathology Research Laboratory, Sant'Andrea University Hospital, Rome, Italy.
authors: Armando
authors: A
authors: Bartolazzi
authors: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors: Giovanna Maria
authors: GM
authors: Pierantoni
authors: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors: Alfredo
authors: A
authors: Fusco
authors: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Silvia
authors: S
authors: Soddu
authors: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.|Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), c/o Sapienza University, Rome, Italy.
authors: Cinzia
authors: C
authors: Rinaldo
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D043171:Chromosomal Instability; D048749:Cytokinesis / Q000502:physiology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: CIN; HIPK2; cytokinesis failure; near-tetraploidy; tumorigenicity