Ishiguro Naoko, Yoshida Haruhiko
Department of Pathobiological Science and Technology, Faculty of Medicine, Tottori University, 86 Nishimachi, Yonago, Tottori 683-8503, Japan.
Department of Pathology, Yonago Medical Center, 4-17-1 Kuzumo, Yonago, Tottori 683-0006, Japan.
Neoplasia. 2016 Oct;18(10):626-635. doi: 10.1016/j.neo.2016.08.001. Epub 2016 Sep 24.
Alveolar soft part sarcoma is an extremely rare soft tissue sarcoma with poor prognosis. It is characterized by the unbalanced recurrent chromosomal translocation der(17)t(X;17)(p11;q25), resulting in the generation of an ASPL-TFE3 fusion gene. ASPL-TFE3 oncoprotein functions as an aberrant transcriptional factor and is considered to play a crucial role in the tumorigenesis of alveolar soft part sarcoma. However, the underlying molecular mechanisms are poorly understood. In this study, we identified p21 (p21) as a direct transcriptional target of ASPL-TFE3. Ectopic ASPL-TFE3 expression in 293 cells resulted in cell cycle arrest and significant increases in protein and mRNA levels of p21. ASPL-TFE3 activated p21 expression in a p53-independent manner through direct transcriptional interactions with the p21 promoter region. When ASPL-TFE3 was expressed in human bone marrow-derived mesenchymal stem cells in a tetracycline-inducible manner, we observed the up-regulation of p21 expression and the induction of senescence-associated β-galactosidase activity. Suppression of p21 significantly decreased the induction of ASPL-TFE3-mediated cellular senescence. Furthermore, ASPL-TFE3 expression in mesenchymal stem cells resulted in a significant up-regulation of proinflammatory cytokines associated with senescence-associated secretory phenotype (SASP). These results show that ASPL-TFE3 regulates cell cycle progression and induces cellular senescence by up-regulating p21 expression. In addition, our data suggest a potential mechanism by which ASPL-TFE3-induced senescence may play a role in tumorigenesis by inducing SASP, which could promote the protumorigenic microenvironment.
肺泡软组织肉瘤是一种极其罕见的软组织肉瘤，预后较差。其特征是反复出现的染色体易位der(17)t(X;17)(p11;q25)失衡，导致ASPL-TFE3融合基因的产生。ASPL-TFE3癌蛋白作为一种异常转录因子，被认为在肺泡软组织肉瘤的肿瘤发生中起关键作用。然而，其潜在的分子机制尚不清楚。在本研究中，我们确定p21为ASPL-TFE3的直接转录靶点。在293细胞中异位表达ASPL-TFE3导致细胞周期停滞，p21的蛋白质和mRNA水平显著增加。ASPL-TFE3通过与p21启动子区域的直接转录相互作用，以p53非依赖的方式激活p21表达。当ASPL-TFE3以四环素诱导的方式在人骨髓间充质干细胞中表达时，我们观察到p21表达上调和衰老相关β-半乳糖苷酶活性的诱导。抑制p21显著降低了ASPL-TFE3介导的细胞衰老诱导。此外，间充质干细胞中ASPL-TFE3的表达导致与衰老相关分泌表型（SASP）相关的促炎细胞因子显著上调。这些结果表明，ASPL-TFE3通过上调p21表达来调节细胞周期进程并诱导细胞衰老。此外，我们的数据提示了一种潜在机制，即ASPL-TFE3诱导的衰老可能通过诱导SASP在肿瘤发生中发挥作用，而SASP可促进促肿瘤微环境。
