Dysregulation of Parkin-mediated mitophagy in thyroid Hurthle cell tumors
Dysregulation of Parkin-mediated mitophagy in thyroid Hurthle cell tumors
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DOI：
10.1093/carcin/bgv122
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发表时间：
2015-11-01
期刊：
影响因子：
4.7
通讯作者：
Shong, Minho
中科院分区：
文献类型：
--
作者：
Lee, Junguee;Ham, Sujin;Shong, Minho
有缺陷的线粒体的异常积累是癌细胞的标志，这在甲状腺Hurthle细胞病变中经常观察到。自噬是一种重要的细胞分解代谢机制，用于降解功能失调的细胞器，并与多种人类疾病有关。目前尚不清楚Hurthle细胞肿瘤中缺陷线粒体的自噬周转是如何调节的。我们的特点的分子标志物，包括Beclin1，LC3，PINK1和帕金，这是所需的自噬或线粒体自噬，在人类甲状腺嗜酸细胞病变的表达模式。为了进行机制研究，我们使用XTC. UC 1细胞（Hurthle细胞肿瘤的唯一体外模型）研究了自噬和线粒体自噬。Beclin1和LC3在Hurthle细胞瘤组织中高表达。XTC. UC 1对饥饿和雷帕霉素处理显示出自噬反应，而它们显示出无效的线粒体自噬激活，这是由PINK 1和Parkin响应CCCP的协调作用触发的。这导致异常线粒体的周转减少。通过对XTC、UC 1和Hurthle细胞肿瘤组织中PARK2基因的遗传分析，研究了线粒体自噬缺陷和线粒体更新的潜在机制。XTC. UC 1和几种肿瘤携带V380L突变，导致功能失调的autoubiquitination和E3连接酶活性降低。一致地，与正常甲状腺细胞相比，Hrthle细胞肿瘤中的癌细胞显示出相当的PINK1表达，但Parkin表达降低。野生型Parkin的引入使XTC. UC 1对CCCP诱导的死亡敏感。本研究为异质性Hrthle细胞肿瘤中嗜酸细胞的形成提供了可能的病因学基础，其原因是线粒体自噬不足导致由线粒体质量控制的功能障碍性Parkin介导的途径引起的异常线粒体的无效周转。
Abnormal accumulation of defective mitochondria is the hallmark of oncocytes, which are frequently observed in thyroid Hurthle cell lesions. Autophagy is an essential cellular catabolic mechanism for the degradation of dysfunctional organelles and has been implicated in several human diseases. It is yet unknown how autophagic turnover of defective mitochondria in Hurthle cell tumors is regulated. We characterized the expression patterns of molecular markers including Beclin1, LC3, PINK1 and Parkin, which are required for autophagy or mitophagy, in human oncocytic lesions of the thyroid. To undertake mechanistic studies, we investigated autophagy and mitophagy using XTC.UC1 cells, the only in vitro model of Hurthle cell tumors. Beclin1 and LC3 were highly expressed in oncocytes of Hurthle cell tumor tissues. XTC.UC1 showed autophagic responses to starvation and rapamycin treatment, whereas they displayed ineffective activation of mitophagy, which is triggered by the coordinated action of PINK1 and Parkin in response to CCCP. This resulted in a decreased turnover of abnormal mitochondria. The mechanisms underlying defective mitophagy and mitochondrial turnover were investigated by genetic analysis of the PARK2 gene in XTC.UC1 and Hurthle cell tumor tissues. XTC.UC1 and several tumors harbored the V380L mutation, resulting in dysfunctional autoubiquitination and decreased E3 ligase activity. Consistently, oncocytes in Hrthle cell tumors displayed comparable expression of PINK1 but decreased Parkin expression in comparison to normal thyrocytes. The introduction of wild-type Parkin sensitized XTC.UC1 to death induced by CCCP. This study provides a possible etiological basis for oncocytic formation in heterogeneous Hrthle cell tumors through insufficient mitophagy leadinto ineffective turnover of aberrant mitochondria caused by dysfunctional Parkin-mediated pathways of mitochondria quality control.