Bladder cancer (BC) is one of the most lethal malignancies worldwide. The poor survival may be due to a high proportion of tumor metastasis. RON and CXCR4 are the key regulators of cell motility in BC, while the relationship between RON and CXCR4 remains elusive. In the present study, immunohistochemistry analysis of BC and adjacent normal tissues found that higher RON expression was positively correlated with CXCR4 expression. Inhibiting and replenishing RON level were used to regulate CXCR4 expression, observing the effects on migration and invasion of BC cells. Overexpression of RON reversed the inhibited cell migration and invasion following siCXCR4 treatment. Conversely, overexpression of CXCR4 restored the inhibition of cell migration and invasion caused by shRON. The activation of RON-MAPK/RSK/CREB pathway was demonstrated in BC cells under MSP treatment. Dual luciferase and CHIP assay showed that p-CREB targeted CXCR4 by binding to its CRE sequence. RON knockdown suppressed BC tumor growth in xenograft mouse tumors, accompanied by reduced expression of CXCR4. In conclusion, our data adds evidence that RON, a membrane tyrosine kinase receptor, promotes BC migration and invasion not only by itself, but also by activating MAPK/RSK/CREB signaling pathway to enhance CXCR4 expression.

中文翻译：

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酪氨酸激酶受体RON激活MAPK/RSK/CREB信号通路增强CXCR4表达促进膀胱癌细胞迁移和侵袭

膀胱癌（BC）是全世界最致命的恶性肿瘤之一。生存率低可能是由于肿瘤转移比例高。RON 和 CXCR4 是 BC 细胞运动的关键调节因子，但 RON 和 CXCR4 之间的关系仍然难以捉摸。在本研究中，对BC和癌旁正常组织的免疫组织化学分析发现，较高的RON表达与CXCR4表达呈正相关。通过抑制和补充RON水平来调节CXCR4的表达，观察对BC细胞迁移和侵袭的影响。RON 的过表达逆转了 siCXCR4 处理后受抑制的细胞迁移和侵袭。相反，CXCR4的过表达恢复了shRON引起的细胞迁移和侵袭的抑制。MSP 处理下的 BC 细胞中证实了 RON-MAPK/RSK/CREB ​​通路的激活。双荧光素酶和 CHIP 测定表明，p-CREB ​​通过与其 CRE 序列结合来靶向 CXCR4。RON 敲低抑制了异种移植小鼠肿瘤中的 BC 肿瘤生长，并伴随着 CXCR4 表达的减少。总之，我们的数据进一步证明，膜酪氨酸激酶受体 RON 不仅自身促进 BC 迁移和侵袭，而且还通过激活 MAPK/RSK/CREB ​​信号通路增强 CXCR4 表达。