SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism.
SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism.
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DOI：
10.3389/fonc.2021.682710
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发表时间：
2021
影响因子：
4.7
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Wang Y;Gao J;Hu S;Zeng W;Yang H;Chen H;Wang S
膀胱癌(BCA)是一种世界范围内常见的恶性肿瘤，由于其固有的生物学侵袭性和特殊的放化疗耐药特征，其存活率很低。更好地了解BCA的发生机制，开发新的诊断和治疗策略，对于改善BCA的临床预后具有重要意义。SLC25家族成员21(SLC25A21)是一种运输C5-C7氧二羧酸盐的载体，据报道与己二酸酸血症有关。然而，SLC25A21在癌症中的潜在作用仍然是绝对未知的。采用实时荧光定量聚合酶链式反应和免疫组织化学方法检测SLC25A21在BCA和正常组织中的表达水平。采用CCK-8比色法、平板集落形成实验、细胞迁移、侵袭实验和实验动物模型检测SLC25A21的体内外生物学功能。通过检测SLC25A21介导的底物亚细胞分布、线粒体膜电位和ROS的产生，探讨SLC25A21在BCA中的作用机制。我们发现SLC25A21在BCA组织中的表达较正常组织下调。BCA患者SLC25A21表达降低与预后不良呈显著正相关。在体外，过表达SLC25A21可显著抑制细胞的增殖、迁移和侵袭，并诱导细胞凋亡。此外，增强的SLC25A21表达显著抑制了异种移植小鼠模型中的肿瘤生长。此外，我们还发现SLC25A21通过诱导线粒体α-KG外流到胞浆，减少氧化应激，激活ROS介导的线粒体依赖的细胞凋亡途径来抑制BCA的生长。我们的发现提供了SLC25A21的表达与BCA之间的第一个联系，并表明SLC25A21在BCA的进展中起着关键的抑制作用，这可能有助于为BCA的干预提供新的靶点。
Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown. The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa. We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway. Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.
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DOI：
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发表时间：
2014-01-21
影响因子：
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作者：
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