Oncotarget

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CFC1 is a cancer stemness-regulating factor in neuroblastoma

Koji Chikaraishi, Hisanori Takenobu, Ryuichi P. Sugino, Kyosuke Mukae, Jesmin Akter, Masayuki Haruta, Masafumi Kurosumi, Takaho A. Endo, Haruhiko Koseki, Naoki Shimojo, Miki Ohira and Takehiko Kamijo _

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Oncotarget. 2017; 8:45046-45059. https://doi.org/10.18632/oncotarget.18464

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Abstract

Koji Chikaraishi1,2, Hisanori Takenobu1,3, Ryuichi P. Sugino1, Kyosuke Mukae1,3, Jesmin Akter1, Masayuki Haruta1,3, Masafumi Kurosumi4, Takaho A. Endo5, Haruhiko Koseki6, Naoki Shimojo2, Miki Ohira1,3 and Takehiko Kamijo1,3

1 Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan

2 Department of Pediatrics, Chiba University, Chiba, Japan

3 Laboratory of Tumor Molecular Biology, Graduate School of Science and Engineering, Saitama University, Saitama, Japan

4 Department of Pathology, Saitama Cancer Center, Saitama, Japan

5 Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

6 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

Correspondence to:

Takehiko Kamijo, email:

Keywords: CFC1, neuroblastoma, cancer stem cells, sphere, Activin A

Received: December 06, 2016 Accepted: May 28, 2017 Published: June 13, 2017

Abstract

Background: Despite the use of aggressive therapy, survival rates among high-risk neuroblastoma (NB) patients remain poor. Cancer stem cells (CSCs) are considered to be critically involved in the recurrence and metastasis of NB and are isolated as NB spheres.

Methods: The gene expression profiling of adherent (control) and sphere-forming primary NB cells was conducted using a gene expression microarray. CFC1, which functions in the development of embryos and decides the left-right axis, was strongly expressed in sphere-forming cells only and was related to the unfavorable prognosis of NB patients. The knockdown and overexpression of CFC1 were performed using a lentiviral system in NB cell lines. Sphere formation, cell proliferation, colony formation in soft agar, and xenograft tumor formation were analyzed.

Results: The overexpression of CFC1 increased sphere formation, cell growth, and colony formation. These phenotypes, particularly sphere formation, and xenograft tumor formation were significantly suppressed by the knockdown of CFC1. CFC1 inhibited Activin A-induced NB cell differentiation and Smad2 phosphorylation in NB cell lines, indicating its involvement in tumorigenesis related to EGF-CFC co-receptor family molecule pathways. Collectively, these results indicate that CFC1 is a candidate molecule for the development of CSC-targeted therapy for NB.


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