The long noncoding RNA TP73-AS1 promotes tumorigenicity of medulloblastoma cells
Mor Varon
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
M.V. and T.L. contributed equally to this workSearch for more papers by this authorTal Levy
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
M.V. and T.L. contributed equally to this workSearch for more papers by this authorGal Mazor
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorHila Ben David
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorRan Marciano
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
The National Institute for Biotechnology in the Negev, Beer Sheva, Israel
Search for more papers by this authorYakov Krelin
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorManu Prasad
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Search for more papers by this authorMoshe Elkabets
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Search for more papers by this authorDavid Pauck
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorUlvi Ahmadov
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorDaniel Picard
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorNan Qin
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorArndt Borkhardt
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorGuido Reifenberger
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorGabriel Leprivier
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorMarc Remke
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorCorresponding Author
Barak Rotblat
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
The National Institute for Biotechnology in the Negev, Beer Sheva, Israel
Correspondence to: Barak Rotblat, Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel, E-mail: [email protected]Search for more papers by this authorMor Varon
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
M.V. and T.L. contributed equally to this workSearch for more papers by this authorTal Levy
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
M.V. and T.L. contributed equally to this workSearch for more papers by this authorGal Mazor
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorHila Ben David
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorRan Marciano
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
The National Institute for Biotechnology in the Negev, Beer Sheva, Israel
Search for more papers by this authorYakov Krelin
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Search for more papers by this authorManu Prasad
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Search for more papers by this authorMoshe Elkabets
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Search for more papers by this authorDavid Pauck
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorUlvi Ahmadov
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorDaniel Picard
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorNan Qin
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorArndt Borkhardt
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorGuido Reifenberger
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorGabriel Leprivier
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorMarc Remke
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorCorresponding Author
Barak Rotblat
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
The National Institute for Biotechnology in the Negev, Beer Sheva, Israel
Correspondence to: Barak Rotblat, Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel, E-mail: [email protected]Search for more papers by this authorAbstract
Medulloblastoma is the most common malignant brain cancer in children. Since previous studies have mainly focused on alterations in the coding genome, our understanding of the contribution of long noncoding RNAs (lncRNAs) to medulloblastoma biology is just emerging. Using patient-derived data, we show that the promoter of lncRNA TP73-AS1 is hypomethylated and that the transcript is highly expressed in the SHH subgroup. Furthermore, high expression of TP73-AS1 is correlated with poor outcome in patients with TP53 wild-type SHH tumors. Silencing TP73-AS1 in medulloblastoma tumor cells induced apoptosis, while proliferation and migration were inhibited in culture. In vivo, silencing TP73-AS1 in medulloblastoma tumor cells resulted in reduced tumor growth, reduced proliferation of tumor cells, increased apoptosis and led to prolonged survival of tumor-bearing mice. Together, our study suggests that the lncRNA TP73-AS1 is a prognostic marker and therapeutic target in medulloblastoma tumors and serves as a proof of concept that lncRNAs are important factors in the disease.
Abstract
What's new?
Long non-coding RNAs (lncRNAs) influence diverse cellular activities, including gene expression and the activity of adjacent genes. Hence, some lncRNAs are implicated in cancer. Here, the lncRNA TP73-AS1 was investigated for a possible functional role in medulloblastoma. TP73-AS1 was found to be overexpressed in medulloblastoma cells, with expression levels correlated to TP73-AS1 hypomethylation. Functionally, TP73-AS1 prevented cell death and promoted proliferation and tumorigenicity of medulloblastoma tumor cells in vitro and in vivo. Mice injected with TP73-AS1-knockdown medulloblastoma tumor cells exhibited reduced tumor growth and improved survival. The findings identify TP73-AS1 as a potential marker and therapeutic target in medulloblastoma.
Supporting Information
| Filename | Description |
|---|---|
| ijc32400-sup-0001-FigureS1.tiffTIFF image, 1.9 MB | Fig. S1 TP73-AS1 effects on TP53 are cell line specific. (A) The indicated cell lines were lysed and analyzed by western blot and the indicated antibodies. HSC70 was used as a loading control. (B) Cell cycle was measured using PI staining and FACS as in Ref. 45 (n = 3; *p < 0.05). (C) ROS levels were measured in the indicated cells using CM-DCFDA staining and FACS. Mean fluorescence are shown (n = 3; p < 0.05). |
| ijc32400-sup-0002-FigureS2.pdfPDF document, 36.6 KB | Fig. S2 TP73-AS1 promotes migration of medulloblastoma tumor cells. Cell migration was measured using a transwell assay (n = 3; p < 0.05). |
| ijc32400-sup-0003-FigureS3.pdfPDF document, 1.3 MB | Fig. S3 TP73-AS1 does not regulate TP73 expression in medulloblastoma. (A) The levels of TP73-AS1 and p73 were determined using qRT-PCR of DAOY cells expressing shSCR or shTP73-AS1. n = 3. (B) Analysis of published RNA-seq data39 obtained from DAOY cells with p73 silencing. (C) Coexpression analysis of TP73-AS1 and p73 levels in two nonoverlapping medulloblastoma cohorts. Analyses performed using R2.47 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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