TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease
| العنوان: | TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease |
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| المؤلفون: | Toshio Suda, Naoto Kuroda, Ying Huang, Hong-Wei Sun, Luh Ade Wilan Krisna, Kimi Araki, Masafumi Oyama, Aiko Sugiyama, Masaya Baba, Martin Lang, Nicole Morris, Tsuyoshi Kadomatsu, Ryoma Kurahashi, Tomomi Kamba, Yoji Nagashima, Yukiko Hasumi, Lilia Ileva, Baktiar O. Karim, Yorifumi Satou, Hisashi Hasumi, Joseph D. Kalen, Yuichi Oike, Ikuma Kato, Mitsuko Furuya, Wenjuan Ma, Takanobu Motoshima, Shintaro Funasaki, Masatoshi Eto, Koshiro Nishimoto, Laura S. Schmidt, W. Marston Linehan, Masahiro Yao |
| المصدر: | Mol Cancer Res |
| بيانات النشر: | American Association for Cancer Research (AACR), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, Apoptosis, Cell Cycle Proteins, TFE3, urologic and male genital diseases, Vandetanib, Translocation, Genetic, Mice, 0302 clinical medicine, Renal cell carcinoma, Tumor Cells, Cultured, Child, Membrane Glycoproteins, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Middle Aged, Prognosis, Kidney Neoplasms, female genital diseases and pregnancy complications, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Survival Rate, Oncology, Proto-Oncogene Proteins c-ret, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, medicine.drug, Adult, Adolescent, Transgene, Article, Young Adult, 03 medical and health sciences, Biomarkers, Tumor, medicine, Animals, Humans, Carcinoma, Renal Cell, neoplasms, Molecular Biology, Transcription factor, Aged, Cell Proliferation, Chromosomes, Human, X, GPNMB, business.industry, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Cancer research, business |
| الوصف: | Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC. |
| تدمد: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-18-1235 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b2c27ab72110a49d4b25a7e9da6bf367 https://doi.org/10.1158/1541-7786.mcr-18-1235 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b2c27ab72110a49d4b25a7e9da6bf367 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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| DOI: | 10.1158/1541-7786.mcr-18-1235 |