The standard-of-care for metastatic muscle-invasive bladder cancer (MIBC) is platinum-based chemotherapy regimens. Acquired resistance that occurs frequently through unidentified mechanisms, however, remains the major obstacle for implementing therapeutic effectiveness. Here, using data mining and analysis on clinical samples, we show that expression of JUND, a core component of activator protein-1 family, was significantly induced in cisplatin (CDDP)-resistant MIBC. Accumulation of nuclear JUND was associated with low post-chemotherapy survival in MIBC patients. In both genetically engineered cell models and murine xenograft models, we provided evidence that bladder cancer (BC) cells with excessive JUND expression were less responsive to CDDP treatment. This CDDP resistance was further demonstrated to be mediated, at least in part, by transactivation of HMOX1 [the gene encoding heme oxygenase-1 (HO-1)], one of the most important antioxidant signalling pathways of cell adaptation to stress. One mutation within the HMOX1 promoter successfully abolished oxidative stress-enhanced and JUND-driven HMOX1 promoter activation, suggesting that this unique site synergized for maximal HO-1 induction in CDDP-challenged BC cells. Overall, our data highlight an indispensible role of JUND, both as a target as a modifier of the oxidative stress signalling, in conferring an adaptive response during the pathogenesis of CDDP resistance in MIBC.

中文翻译：

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HMOX1的JUND依赖性上调与肌肉浸润性膀胱癌的顺铂耐药性相关。

转移性肌肉浸润性膀胱癌（MIBC）的护理标准是基于铂的化疗方案。然而，通过未知机制经常发生的获得性耐药仍然是实现治疗效果的主要障碍。在这里，使用数据挖掘和对临床样本的分析，我们表明，在顺铂（CDDP）耐药的MIBC中，诱导蛋白1家族的核心成分JUND的表达被显着诱导。MIBC患者的核JUND积累与化疗后存活率低有关。在基因工程细胞模型和鼠异种移植模型中，我们提供的证据表明，JUND表达过多的膀胱癌细胞（BC）对CDDP治疗的反应较弱。进一步证明这种CDDP抗性至少部分地是通过介导的 通过反式激活HMOX1 [编码血红素加氧酶-1（HO-1）的基因]，HMOX1是细胞适应压力的最重要的抗氧化信号途径之一。HMOX1启动子内的一个突变成功消除了氧化应激增强和JUND驱动的HMOX1启动子激活，表明该独特位点在CDDP攻击的BC细胞中协同最大HO-1诱导。总体而言，我们的数据突显了JUND在MIBC的CDDP耐药性发病机理中赋予适应性应答的过程中，JUND作为氧化应激信号转导的靶标，具有不可或缺的作用。HMOX1启动子内的一个突变成功消除了氧化应激增强和JUND驱动的HMOX1启动子激活，表明该独特位点在CDDP攻击的BC细胞中协同最大HO-1诱导。总体而言，我们的数据突显了JUND在MIBC的CDDP耐药性发病机理中赋予适应性应答的过程中，JUND作为氧化应激信号转导的靶标，具有不可或缺的作用。HMOX1启动子内的一个突变成功消除了氧化应激增强和JUND驱动的HMOX1启动子激活，表明该独特位点在CDDP攻击的BC细胞中协同最大HO-1诱导。总体而言，我们的数据突显了JUND在MIBC的CDDP耐药性发病机理中赋予适应性应答的过程中，JUND作为氧化应激信号转导的靶标，具有不可或缺的作用。