骨肉瘤是一种高度侵袭性的恶性肿瘤，在儿童中常见，残疾率和死亡率高。最近的研究表明，三分体结构域包含家族基因(TRIMs)在几种癌症的发生中起着关键作用。TRIM26是TRIMs家族基因之一，更频繁地被报道具有抑制肿瘤作用，但其在骨肉瘤进展中的详细功能作用仍然不明，需要进一步研究。本研究发现TRIM26在骨肉瘤组织和细胞中明显下调。生存分析显示TRIM26的高表达与更好的预后相关，并且其表达是骨肉瘤中独立的保护因素。功能分析证明TRIM26的过表达通过抑制EMT过程和MEK/ERK信号转导来抑制骨肉瘤细胞的增殖和侵袭。相反，TRIM26的沉默则产生相反的效应。Trp-Asp重复蛋白家族的成员RACK1被鉴定为TRIM26的一个新的靶标。TRIM26能与RACK1相互作用并促进RACK1的降解，从而使MEK/ERK信号转导失活。RACK1的过表达可减弱TRIM26过表达对p-MEK1/2和p-ERK1/2的抑制作用，而RACK1的沉默可在一定程度上减弱TRIM26沉默引起的p-MEK1/2和p-ERK1/2的上调效应。进一步的一系列功能增强和减弱实验表明，当RACK1过表达时，TRIM26上调细胞中的恶性行为包括细胞增殖和侵袭性能得到逆转，而RACK1的沉默则减弱了TRIM26沉默诱导的骨肉瘤细胞中恶性表型的增加。总之，我们的研究表明TRIM26通过促进RACK1的蛋白骨架降解抑制了骨肉瘤的进展，从而导致MEK/ERK信号转导的失活，阻碍了EMT过程。© 2023. 作者。

Osteosarcoma is a highly aggressive malignant tumor that is common in the pediatric population and has a high rate of disability and mortality. Recent studies have suggested that the tripartite motif-containing family genes (TRIMs) play critical roles in oncogenesis in several cancers. TRIM26, one of the TRIMs family genes, was more frequently reported to exert a tumor-suppressive role, while its detailed functional roles in the osteosarcoma progression were still unknown and require further investigation. Herein, we found that TRIM26 was markedly downregulated in osteosarcoma tissues and cells. Survival analysis revealed that higher expression of TRIM26 was associated with better prognosis and its expression was an independent protective factor in osteosarcoma. Functional analysis demonstrated that overexpression of TRIM26 inhibited osteosarcoma cell proliferation and invasion via inhibiting the EMT process and MEK/ERK signaling. In contrast, the silence of TRIM26 caused the opposite effect. RACK1, a member of the Trp-Asp repeat protein family, was identified as a novel target of TRIM26. TRIM26 could interact with RACK1 and accelerate the degradation of RACK1, thus inactivation of MEK/ERK signaling. Overexpression of RACK1 could attenuate the inhibitory effect of TRIM26 overexpression on p-MEK1/2 and p-ERK1/2, and silence of RACK1 could partly impair the effect of TRIM26 knockdown-induced upregulation of p-MEK1/2 and p-ERK1/2. Further, a series of gain- and loss-of-function experiments showed that decreased malignant behaviors including cell proliferation and invasion in TRIM26-upregulated cells were reversed when RACK1 was overexpressed, whereas RACK1 knockdown diminished the increased malignant phenotypes in TRIM26-silenced osteosarcoma cells. In conclusion, our study indicated that TRIM26 inhibited osteosarcoma progression via promoting proteasomal degradation of RACK1, thereby resulting in inactivation of MEK/ERK signaling, and impeding the EMT process.© 2023. The Author(s).