Oncotarget

Research Papers:

Development of zebrafish medulloblastoma-like PNET model by TALEN-mediated somatic gene inactivation

Jaegal Shim, Jung-Hwa Choi, Moon-Hak Park, Hyena Kim, Jong Hwan Kim, Seon-Young Kim, Dongwan Hong, Sunshin Kim, Ji Eun Lee, Cheol-Hee Kim _, Jeong-Soo Lee and Young-Ki Bae

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Oncotarget. 2017; 8:55280-55297. https://doi.org/10.18632/oncotarget.19424

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Abstract

Jaegal Shim1,*, Jung-Hwa Choi2,*, Moon-Hak Park10, Hyena Kim10, Jong Hwan Kim3, Seon-Young Kim3, Dongwan Hong4, Sunshin Kim5, Ji Eun Lee6, Cheol-Hee Kim2, Jeong-Soo Lee7,8,9 and Young-Ki Bae1,10

1Comparative Biomedicine Research Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea

2Department of Biology, Chungnam National University, Daejeon, Republic of Korea

3Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

4Clinical Genomic Analysis Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea

5Precision Medicine Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea

6Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Gangnam-gu, Seoul, Republic of Korea

7Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

8Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Seoul, Republic of Korea

9Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea

10Tumor Microenviroment Research Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea

*These authors contributed equally to this work

Correspondence to:

Cheol-Hee Kim, email: [email protected]

Jeong-Soo Lee, email: [email protected]

Young-Ki Bae, email: [email protected]

Keywords: medulloblastoma, PNET, MPNST, TALEN, somatic inactivation

Received: November 22, 2016     Accepted: July 11, 2017     Published: July 21, 2017

ABSTRACT

Genetically engineered animal tumor models have traditionally been generated by the gain of single or multiple oncogenes or the loss of tumor suppressor genes; however, the development of live animal models has been difficult given that cancer phenotypes are generally induced by somatic mutation rather than by germline genetic inactivation. In this study, we developed somatically mutated tumor models using TALEN-mediated somatic gene inactivation of cdkn2a/b or rb1 tumor suppressor genes in zebrafish. One-cell stage injection of cdkn2a/b-TALEN mRNA resulted in malignant peripheral nerve sheath tumors with high frequency (about 39%) and early onset (about 35 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Injection of rb1-TALEN mRNA also led to the formation of brain tumors at high frequency (58%, 31 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Analysis of each tumor induced by somatic inactivation showed that the targeted genes had bi-allelic mutations. Tumors induced by rb1 somatic inactivation were characterized as medulloblastoma-like primitive neuroectodermal tumors based on incidence location, histopathological features, and immunohistochemical tests. In addition, 3′ mRNA Quanti-Seq analysis showed differential activation of genes involved in cell cycle, DNA replication, and protein synthesis; especially, genes involved in neuronal development were up-regulated.


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