Research Papers:

In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma

Jason K. Sa _, Yeup Yoon, Misuk Kim, Yeonghwan Kim, Hee Jin Cho, Jin-Ku Lee, Gi-Soo Kim, Suji Han, Woon Jin Kim, Yong Jae Shin, Kyeung Min Joo, Patrick J. Paddison, Tohru Ishitani, Jeongwu Lee and Do-Hyun Nam

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Oncotarget. 2015; 6:20145-20159. https://doi.org/10.18632/oncotarget.3980

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Jason K. Sa1,2,3,*, Yeup Yoon1,*, Misuk Kim2,3,*, Yeonghwan Kim4,*, Hee Jin Cho1,2,3, Jin-Ku Lee2,3, Gi-Soo Kim3, Suji Han1,2,3, Woon Jin Kim1,2,3, Yong Jae Shin2,3, Kyeung Min Joo1,2,3, Patrick J. Paddison5, Tohru Ishitani6, Jeongwu Lee4, Do-Hyun Nam1,2,3,7

1Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea

2Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

3Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea

4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

5Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

6Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

7Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Do-Hyun Nam, e-mail: [email protected]

Jeongwu Lee, e-mail: [email protected]

Keywords: glioblastoma, RNA interference screen, Nemo-like kinase, stemness, mesenchymal

Received: April 23, 2015     Accepted: May 06, 2015     Published: May 19, 2015


Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/β-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen.

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