TFE3融合蛋白对CDKN1A/p21的转录上调作用使TFE3重排的肾细胞癌病情恶化。
Transcriptionally up-regulation of CDKN1A/p21 by TFE3 fusion proteins worsened TFE3-rearranged renal cell carcinoma.
作者信息
Lu Yanwen, Ma Wenliang, Chen Yi, Dong Xiang, Pan Xinghe, Yang Lei, Zhou Shuoming, Liu Ning, Li Dongmei, Gan Weidong
机构信息
Department of Urology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, People's Republic of China.
Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
出版信息
Sci Rep. 2025 Aug 17;15(1):30067. doi: 10.1038/s41598-025-13302-x.
The TFE3-rearranged renal cell carcinoma (TFE3-rRCC), which is an uncommon and aggressive form of kidney cancer, has an unfavorable prognosis. It has been shown that CDKN1A/p21 is high-expressed in TFE3-rRCC, however, the exact mechanism and the role of CDKN1A/p21 in TFE3-rRCC remain unclear. Our results indicated that the TFE3 fusions exacerbated TFE3-rRCC by transcriptionally upregulating CDKN1A/p21 expression. In terms of the mechanism, CDKN1A/p21 was a target gene of TFE3 fusions with positive regulation. Activation of AKT led to the cytoplasmic localization of highly expressed CDKN1A/p21, promoting TFE3-rRCC progression by anti-apoptosis and facilitating migration. Additionally, the remaining nuclear CDKN1A/p21 induced cellular senescence (CS) and secretion of senescence-associated secretory phenotype (SASP) factors, particularly IL-6 and IL-8, which recruited inhibitory immune cells and remodeled tumor microenvironment. This research presents that upregulation of CDKN1A/p21 transcriptionally by TFE3 fusions facilitates the progression of TFE3-rRCC by inducing anti-apoptosis, migration and CS, thus provides a promising target for treating TFE3-rRCC.
TFE3 重排肾细胞癌（TFE3-rRCC）是一种罕见且侵袭性强的肾癌形式，预后不佳。已有研究表明，CDKN1A/p21 在 TFE3-rRCC 中高表达，然而，CDKN1A/p21 在 TFE3-rRCC 中的具体机制和作用仍不清楚。我们的研究结果表明，TFE3 融合通过转录上调 CDKN1A/p21 的表达加剧了 TFE3-rRCC 的发展。在机制方面，CDKN1A/p21 是 TFE3 融合的靶基因，具有正向调控作用。AKT 的激活导致高表达的 CDKN1A/p21 定位于细胞质，通过抗凋亡和促进迁移来推动 TFE3-rRCC 的进展。此外，剩余的核 CDKN1A/p21 诱导细胞衰老（CS）和分泌衰老相关分泌表型（SASP）因子，特别是 IL-6 和 IL-8，它们招募抑制性免疫细胞并重塑肿瘤微环境。本研究表明，TFE3 融合转录上调 CDKN1A/p21 通过诱导抗凋亡、迁移和 CS 促进 TFE3-rRCC 的进展，从而为治疗 TFE3-rRCC 提供了一个有前景的靶点。
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