MicroRNA142-3p Promotes Tumor-Initiating and Radioresistant Properties in Malignant Pediatric Brain Tumors

Author:

Lee Yi-Yen12,Yang Yi-Ping13,Huang Ming-Chao24,Wang Mong-Lien4,Yen Sang-Hue45,Huang Pin-I15,Chen Yi-Wei15,Chiou Shih-Hwa134,Lan Yuan-Tzu13,Ma Hsin-I6,Shih Yang-Hsin47,Chen Ming-Teh47

Affiliation:

1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

2. Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

3. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

4. School of Medicine, National Yang-Ming University, Taipei, Taiwan

5. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

6. Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan

7. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

Abstract

Primary central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT) is an extremely malignant pediatric brain tumor observed in infancy and childhood. It has been reported that a subpopulation of CD133+ cells isolated from ATRT tumors present with cancer stem-like and radioresistant properties. However, the exact biomolecular mechanisms of ATRT or CD133-positive ATRT (ATRT-CD133+) cells are still unclear. We have previously shown that ATRT-CD133+ cells have pluripotent differentiation ability and the capability of malignant cells to be highly resistant to ionizing radiation (IR). By using microRNA array and quantitative RT-PCR in this study, we showed that expression of miR142-3p was lower in ATRT-CD133+ cells than in ATRT-CD133- cells. miR142-3p overexpression significantly inhibited the self-renewal and tumorigenicity of ATRT-CD133+ cells. On the contrary, silencing of endogenous miR142-3p dramatically increased the tumor-initiating and stem-like cell capacities in ATRT cells or ATRT-CD133- cells and further promoted the mesenchymal transitional and radioresistant properties of ATRT cells. Most importantly, therapeutic delivery of miR142-3p in ATRT cells effectively reduced its lethality by blocking tumor growth, repressing invasiveness, increasing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice. These results demonstrate the prospect of developing novel miRNA-based strategies to block the stem-like and radioresistant properties of malignant pediatric brain cancer stem cells.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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