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

Abstract

Xp11.2 translocation renal cell carcinoma (Xp11 tRCC ) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE 3 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 ‐ TFE 3 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 ‐ TFE 3 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 TFE 3 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 ‐ TFE 3 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 .

Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity

“…To investigate roles of ANGPTL2 in development and progression of tRCC, we generated Chd16-Cre/ Rosa LSL-PRCC-TFE3/+ mice that specifically induce the PRCC-TFE3 fusion gene in renal tubular epithelial cells (Supplemental Fig. S1A; Baba et al 2019;Kurahashi et al 2019). Chd16-Cre/Rosa LSL-PRCC-TFE3/+ mice developed renal cell carcinoma characterized by dilated renal tubules and cyst formation by 40 wk of age, with an incidence of 100%, and their median survival time was 344 d. To evaluate ANGPTL2 function in renal cancer progression, we crossed Chd16-Cre/Rosa LSL-PRCC-TFE3/+ mice with ANGPTL2 mutant mice (either Angptl2 −/− or Angptl2 F/F mice) to achieve ANGPTL2 deficiency in either the whole body or specifically in renal tubular epithelial cells, respectively ( Fig.…”

“…Genetically engineered mice used in this study were: Angptl2 -/mice (Tabata et al 2009) on a C57BL/6N background, Pirb −/− mice (Endo et al 2008) (kindly provided by Dr. Takai [Tohoku University]) on a C57BL/6N background, Rosa LSL-PRCC-TFE3/+ mice on a C57BL/6N background (Kurahashi et al 2019), Angptl2 F/F mice (Tian et al 2016) on a C57BL/6J background, and Tg mice overexpressing Cre driven by the murine Cad-herin16 promoter (Cdh16-Cre) (Shao et al 2002) on a C57BL/ 6N background. Male C57BL/6N mice were purchased from CLEA (Japan).…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…Moreover, urinary exosomal miR-126-3p combined with miR-486-5p could discriminate ccRCC from benign lesions (Butz et al, 2016). Similarly, other more recent studies have reported that urinary exosomal miR-30c-5p and miR-204-5p might serve as the diagnostic markers for early-stage ccRCC (in a human study) and Xp11.2 translocation RCC (in a murine model), respectively (Kurahashi et al, 2019;Song et al, 2019). In addition, two consistent studies in humans have revealed that serum exosomal miR-224 and miR-210 could serve as the prognostic and diagnostic biomarkers for ccRCC (Fujii et al, 2017;Wang X. et al, 2019).…”

Back-Splicing Transcript Isoforms (Circular RNAs) Affect Biologically Relevant Pathways and Offer an Additional Layer of Information to Stratify NMIBC Patients

“…Additionally, the duo of miR-204-5p/211-5p has recently been reported to be involved in resistance to BRAF inhibition (40). Hence, circRNAs harboring target sites for miR-204-5p/211-5p can have important implications for tumor treatment and progression (41,42).…”