Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.
Clin Transl Med. 2022 Apr;12(4):e797. doi: 10.1002/ctm2.797.
The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age-dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC.
The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity.
When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression-free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin-related modifier (SUMO)-specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC-TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC-TFE3 tRCC.
Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC-TFE3 fusion protein.
Xp11.2 易位/TFE3 基因融合相关性肾细胞癌（RCC）的侵袭性具有年龄依赖性，与生殖内分泌激素的整体趋势相似。因此，本研究主要关注雄激素和雄激素受体（AR）对 Xp11.2 易位 RCC（Xp11.2 tRCC）进展的影响及其潜在机制。
首先利用 Xp11.2 tRCC 细胞系和组织评估雄激素和 AR 对 Xp11.2 tRCC 细胞增殖和迁移的影响。由于转录因子增强子 3（TFE3）融合蛋白在 Xp11.2 tRCC 中发挥关键作用，我们重点研究了 AR 和 TFE3 表达和转录活性的调节作用。
当 Xp11.2 tRCC 细胞用二氢睾酮处理时，观察到细胞增殖、侵袭和迁移增加。与透明细胞 RCC 相比，Xp11.2 tRCC 组织中 AR 的阳性率更高，其表达与 Xp11.2 tRCC 的无进展生存期呈负相关。进一步的研究表明，AR 通过小泛素相关修饰酶（SUMO）特异性蛋白酶 1 可正向调节 TFE3 融合蛋白的转录活性，诱导 TFE3 融合蛋白的去 SUMO 化。另一方面，AR 负调控的 UCHL1 可在 PRCC-TFE3 融合蛋白的去泛素化降解中发挥作用。因此，AR 抑制剂 MDV3100 和 UCHL1 抑制剂 6RK73 的联合应用可有效延缓 Xp11.2 tRCC 的进展，特别是 PRCC-TFE3 tRCC。
雄激素和 AR 可促进 Xp11.2 tRCC 的进展，可能成为 Xp11.2 tRCC 的新治疗靶点。AR 拮抗剂 MDV3100 和 UCHL1 抑制剂 6RK73 的联合应用增加了 PRCC-TFE3 融合蛋白的 SUMO 化和泛素化。
