Protective effects of SS-31 against SDHB suppression-mitochondrial dysfunction-EndMT axis-modulated CBT sclerosis and progression.
Protective effects of SS-31 against SDHB suppression-mitochondrial dysfunction-EndMT axis-modulated CBT sclerosis and progression.
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发表时间：
2020
影响因子：
2.2
通讯作者：
Hanfei Tang;Chao Fang;Song Xue;Gefei Zhao;Zhenyu Shi;W. Fu;Pengfei Zhang;Xiao Tang;D. Guo-D.-G
中科院分区：
文献类型：
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作者：
Hanfei Tang;Chao Fang;Song Xue;Gefei Zhao;Zhenyu Shi;W. Fu;Pengfei Zhang;Xiao Tang;D. Guo-D.-G
颈动脉体瘤（CBT）的硬化变体的特征是广泛的基质硬化，这导致了一种罕见的生长模式，非常类似于浸润性恶性肿瘤。然而，其临床意义和机制尚不清楚。在这项研究中，我们提供了SS-31对SDHB抑制-线粒体功能障碍-EndMT轴调节的CBT硬化和进展发挥保护作用的证据。在人类CBT标本中，硬化程度与复发、死亡、系统性转移和无重大不良事件生存率降低、SDHB表达降低和EndMT加重一致相关。在人脐静脉内皮细胞（HUVECs）中，SDHB KD加重了缺氧诱导的EndMT、线粒体功能障碍和代谢转换，而SS-31处理可显著减轻SDHB KD和缺氧引起的这些变化。在CBT的患者来源的异种移植物（PDX）小鼠模型中，我们还观察到硬化性颈动脉体瘤（SCBT）组中的肿瘤生长速度和EndMT的程度、线粒体功能障碍和代谢转换比常规颈动脉体瘤（CCBT）组增加。SS-31治疗可通过挽救线粒体功能障碍诱导的EndMT而显著延缓SCBT的进展。总之，这些结果表明，SDHB抑制-线粒体功能障碍-EndMT轴是CBT硬化和进展的关键部分，而靶向药物SS-31对上述轴发挥抑制作用，这为预防和治疗CBT恶性肿瘤开辟了新的策略。
Sclerosis variant in carotid body tumor (CBT) is characterized by extensive stromal sclerosis, which results in an uncommon pattern of growth that closely resembles that of an invasive malignant neoplasm. However, the clinical significance and the mechanism remains unclear. In this study, we provide evidence that SS-31 exerts protective effects against SDHB suppression-mitochondrial dysfunction-EndMT axis-modulated CBT sclerosis and progression. In human CBT specimens, sclerosis extent was consistently related to decreased recurrence-, death-, systematic metastasis-, and major adverse event-free survival, decreased SDHB expression, and aggravated EndMT. In human umbilical vein endothelial cells (HUVECs), SDHB KD aggravated hypoxia-induced EndMT, mitochondrial dysfunction and metabolic switch, while SS-31 treatment could significantly attenuate these changes caused by SDHB KD and hypoxia. In patient-derived xenograft (PDX) mice models of CBT, we also observed increased tumor growth speed and extent of EndMT, mitochondrial dysfunction, and metabolic switch in sclerosing carotid body tumor (SCBT) group than in conventional carotid body tumor (CCBT) group. And treating with SS-31 could significantly retard SCBT progression by rescuing the mitochondrial dysfunction-induced EndMT. Altogether, these results show that SDHB suppression-mitochondrial dysfunction-EndMT axis is a critical part of the CBT sclerosis and progression, while mitochondria-targeted drug SS-31 exerts an inhibitive effect on the above-mentioned axis, which opens new strategies to prevent and treat malignancies of CBT.