Osteosarcoma is the most common malignant bone tumour, and the metastasis of osteosarcoma is an important cause of death. Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy. In this study, we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism. First, we found that the key rate-limiting enzyme of mevalonate signalling, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was highly expressed in osteosarcoma cells, and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells. Next, we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells. We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization. Moreover, we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA. Finally, we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells, as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice. Taken together, our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA. Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.

骨肉瘤是最常见的恶性骨肿瘤，骨肉瘤的转移是导致死亡的重要原因。有证据表明，甲羟戊酸途径被高度激活，有望成为肿瘤治疗的新靶点。在这项研究中，我们研究了甲羟戊酸信号传导对骨肉瘤转移的影响及其分子机制。首先，我们发现甲羟戊酸信号传导的关键限速酶 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 在骨肉瘤细胞中高表达，辛伐他汀抑制 HMGCR 显着抑制 143B 细胞的运动。接下来，我们发现骨肉瘤细胞中 YAP1 活性显着上调，并且 YAP1 敲低抑制了 143B 细胞的运动。我们还发现甲羟戊酸通路通过调节 YAP1 磷酸化和细胞定位来调节 143B 细胞的运动性。此外，我们发现 YAP1 的活性受到甲羟戊酸途径的调节，通过调节 RhoA 的细胞膜定位。最后，我们证明了抑制甲羟戊酸途径显着减少了 143B 细胞的肺转移，这反映在转移结节的发生率和数量减少以及裸鼠存活时间的增加上。总之，我们的研究结果表明，甲羟戊酸途径可以通过 RhoA 激活 YAP1 来促进骨肉瘤的转移。抑制甲羟戊酸途径可能是治疗骨肉瘤转移的有希望的策略。我们发现 YAP1 的活性是由甲羟戊酸途径通过调节 RhoA 的细胞膜定位来调节的。最后，我们证明了抑制甲羟戊酸途径显着减少了 143B 细胞的肺转移，这反映在转移结节的发生率和数量减少以及裸鼠存活时间的增加上。总之，我们的研究结果表明，甲羟戊酸途径可以通过 RhoA 激活 YAP1 来促进骨肉瘤的转移。抑制甲羟戊酸途径可能是治疗骨肉瘤转移的有希望的策略。我们发现 YAP1 的活性是由甲羟戊酸途径通过调节 RhoA 的细胞膜定位来调节的。最后，我们证明了抑制甲羟戊酸途径显着减少了 143B 细胞的肺转移，这反映在转移结节的发生率和数量减少以及裸鼠存活时间的增加上。总之，我们的研究结果表明，甲羟戊酸途径可以通过 RhoA 激活 YAP1 来促进骨肉瘤的转移。抑制甲羟戊酸途径可能是治疗骨肉瘤转移的有希望的策略。正如转移性结节的发生率和数量减少以及裸鼠存活时间增加所反映的那样。总之，我们的研究结果表明，甲羟戊酸途径可以通过 RhoA 激活 YAP1 来促进骨肉瘤的转移。抑制甲羟戊酸途径可能是治疗骨肉瘤转移的有希望的策略。正如转移性结节的发生率和数量减少以及裸鼠存活时间增加所反映的那样。总之，我们的研究结果表明，甲羟戊酸途径可以通过 RhoA 激活 YAP1 来促进骨肉瘤的转移。抑制甲羟戊酸途径可能是治疗骨肉瘤转移的有希望的策略。