Mitochondrial Superoxide Dismutase Has a Protumorigenic Role in Ovarian Clear Cell Carcinoma.
Mitochondrial Superoxide Dismutase Has a Protumorigenic Role in Ovarian Clear Cell Carcinoma.
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DOI：
10.1158/0008-5472.can-14-3799
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Hempel N
中科院分区：
文献类型：
--
作者：
Hemachandra LP;Shin DH;Dier U;Iuliano JN;Engelberth SA;Uusitalo LM;Murphy SK;Hempel N
上皮性卵巢癌（EOC）是女性癌症死亡的第四大原因，包括不同的组织学亚型，其遗传特征和起源组织差异很大。因此，必须了解这些不同疾病的病因。卵巢透明细胞癌（OCCC）是一种非常侵袭性的亚型，占EOC的>10%。在本研究中，我们发现，线粒体超氧化物歧化酶（SOD 2）是高表达的OCCC相比，其他EOC亚型。Sod 2是一种抗氧化酶，可将高活性超氧化物（O2·−）转化为过氧化氢（H2 O2）和氧气（O2），我们的数据表明，Sod 2在OCCC中具有促肿瘤发生和转移作用。在绒毛尿囊膜（CAM）模型中抑制Sod 2表达减少OCCC ES-2细胞肿瘤生长和转移。类似地，细胞增殖、迁移、球状体附着和在胶原上的生长以及Akt磷酸化随着Sod 2表达的降低而显著降低。从机制上讲，我们发现Sod 2在支持OCCC致瘤性和转移扩散方面具有双重功能。首先，Sod 2通过清除O2·−来维持高功能的线粒体，以支持OCCC的高代谢活性。其次，Sod 2改变稳态ROS平衡以驱动H2 O2介导的迁移。虽然这种更高的稳态H2 O2驱动促转移行为，但它也为OCCC提供了一把双刃剑，因为它推动了细胞内H2 O2阈值，使外源性H2 O2源能够更快速地杀死OCCC。了解抗氧化剂和活性氧的复杂相互作用，可能会提供新的治疗策略，以追求这种组织学EOC亚型的治疗。
Epithelial ovarian cancer (EOC) is the fourth leading cause of death due to cancer in women and comprises distinct histological subtypes, which vary widely in their genetic profiles and tissues of origin. It is therefore imperative to understand the etiology of these distinct diseases. Ovarian clear cell carcinoma (OCCC), a very aggressive subtype, comprises >10% of EOCs. In the present study we show that mitochondrial superoxide dismutase (Sod2) is highly expressed in OCCC compared to other EOC subtypes. Sod2 is an antioxidant enzyme that converts highly reactive superoxide (O2•−) to hydrogen peroxide (H2O2) and oxygen (O2), and our data demonstrate that Sod2 is pro-tumorigenic and -metastatic in OCCC. Inhibiting Sod2 expression reduces OCCC ES-2 cell tumor growth and metastasis in a chorioallantoic membrane (CAM) model. Similarly, cell proliferation, migration, spheroid attachment and outgrowth on collagen, and Akt-phosphorylation are significantly decreased with reduced expression of Sod2. Mechanistically, we show that Sod2 has a dual function in supporting OCCC tumorigenicity and metastatic spread. First, Sod2 maintains highly functional mitochondria, by scavenging O2•−, to support the high metabolic activity of OCCC. Secondly, Sod2 alters the steady-state ROS balance to drive H2O2-mediated migration. While this higher steady-state H2O2 drives pro-metastatic behavior it also presents a doubled-edged sword for OCCC, as it pushed the intracellular H2O2 threshold to enable more rapid killing by exogenous sources of H2O2. Understanding the complex interaction of antioxidants and ROS may provide novel therapeutic strategies to pursue for the treatment of this histological EOC subtype.