LncRNA MT1DP Aggravates Cadmium‐Induced Oxidative Stress by Repressing the Function of Nrf2 and is Dependent on Interaction with miR‐365,Advanced Science

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LncRNA MT1DP Aggravates Cadmium‐Induced Oxidative Stress by Repressing the Function of Nrf2 and is Dependent on Interaction with miR‐365
Advanced Science ( IF 14.3 ) Pub Date : 2018-04-24 , DOI: 10.1002/advs.201800087
Ming Gao _{1,

2} , Changying Li ₃ , Ming Xu _{1,

2} , Yun Liu _{1,

4} , Min Cong ₃ , Sijin Liu _{1,

2}

Affiliation

Although cadmium (Cd)‐induced hepatoxicity is well established, pronounced knowledge gaps remain existed regarding the inherent cellular signaling that dictates Cd toxicity. Specifically, the molecular basis for determining the equilibrium between prosurvival and proapoptotic signaling remains poorly understood. Thus, it is recently revealed that long non‐coding RNA (lncRNA) MT1DP, a pseudogene in the metallothionein (MT) family, promoted Cd‐induced cell death through activating the RhoC‐CCN1/2‐AKT pathway and modulating MT1H induction. Here, first the dependency of MT1DP induction on MTF1, an important transcriptional factor in driving the mRNA expression of MT1 members is defined. Additionally, a bridge molecule between MT1DP and nuclear factor erythroid 2‐related factor 2 (Nrf2) is established: miR‐365. Mechanistically, MT1DP induction under Cd stress decreases the nuclear factor erythroid 2‐related factor 2 (Nrf2) level to evoke oxidative stress through the elevation of miR‐365, which acted to repress the Nrf2 level via direct binding to its 3'UTR. In contrast to the competing endogenous RNA (ceRNA) mechanism, a new mechanism is proposed: MT1DP elevated the miR‐365 level though stabilizing its RNA via direct binding. Collectively, the combined data demonstrate a crucial role of MT1DP in reducing the Nrf2‐mediated protection of cells, and this is dependent on the interplay with miR‐365. Hence, the study further expands the knowledge of inducible endogenous lncRNA in modulating oxidative stress.

中文翻译：

LncRNA MT1DP 通过抑制 Nrf2 的功能加剧镉诱导的氧化应激，并且依赖于与 miR-365 的相互作用

尽管镉 (Cd) 诱导的肝毒性已得到充分证实，但关于决定镉毒性的固有细胞信号传导仍然存在明显的知识差距。具体而言，确定促存活和促凋亡信号传导之间平衡的分子基础仍然知之甚少。因此，最近发现长非编码RNA（lncRNA）MT1DP（金属硫蛋白（MT）家族中的一个假基因）通过激活RhoC-CCN1/2-AKT途径和调节MT1H诱导来促进Cd诱导的细胞死亡。在这里，首先定义了 MT1DP 诱导对 MTF1 的依赖性，MTF1 是驱动 MT1 成员 mRNA 表达的重要转录因子。此外，还建立了 MT1DP 和核因子红细胞 2 相关因子 2 (Nrf2) 之间的桥梁分子：miR-365。从机制上讲，镉胁迫下的 MT1DP 诱导降低了核因子红细胞 2 相关因子 2 (Nrf2) 水平，通过提高 miR-365 诱发氧化应激，而 miR-365 通过直接结合其 3'UTR 来抑制 Nrf2 水平。与竞争性内源性 RNA (ceRNA) 机制相反，提出了一种新机制：MT1DP 通过直接结合稳定其 RNA，从而提高 miR-365 水平。总的来说，综合数据表明 MT1DP 在减少 Nrf2 介导的细胞保护方面发挥着至关重要的作用，这取决于与 miR-365 的相互作用。因此，该研究进一步扩展了诱导型内源性lncRNA在调节氧化应激方面的知识。

更新日期：2018-04-24

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