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Cancer Sci. 2019 Jun;110(6):1897-1908. doi: 10.1111/cas.14026. Epub 2019 May 24.

MicroRNA-204-5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma.

Author information

1
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
2
Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
3
Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
4
International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
5
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
6
Department of Molecular Biology, University of Occupational and Environmental Health, Kitakyushu, Japan.
7
Center for Clinical Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
8
Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
9
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
10
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
11
Basic Science Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, USA.
12
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
13
Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.

Abstract

Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early-stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC-TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)-204-5p levels in urinary exosomes of 40-week-old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA-204-5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR-204-5p-containing exosomes. Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR-204-5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC-TFE3 fusion gene. These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.

KEYWORDS:

Xp11 tRCC; biomarker; exosome; miRNA; urine

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