mGPDH Deficiency leads to melanoma metastasis via induced NRF2.
mGPDH Deficiency leads to melanoma metastasis via induced NRF2.
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mGPDH 缺乏通过诱导 NRF2 导致黑色素瘤转移
DOI：
10.1111/jcmm.16542
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发表时间：
2021-06
影响因子：
5.3
通讯作者：
Long M
中科院分区：
文献类型：
--
作者：
Li X;Zhou L;Zhang Y;He X;Lu H;Zhang L;Tian Y;Liu X;Zheng H;Shao J;Long M
氧化应激对癌症发生和黑色素瘤的进展具有关键影响，侵袭性恶性黑色素瘤的活性归因于其高转移能力。在一些癌细胞系中的某些发现表明，线粒体呼吸链的一个组分——线粒体甘油-3-磷酸脱氢酶（mGPDH）也能调节氧化应激。然而，mGPDH在黑色素瘤中的作用仍不明确。在此，我们报道与正常皮肤相比，人皮肤黑色素瘤中的mGPDH蛋白水平降低，与原发性黑色素瘤相比，转移性黑色素瘤中的mGPDH蛋白水平也降低。我们的体内和体外实验表明，mGPDH的缺失加速了黑色素瘤的迁移和侵袭，但不影响增殖或凋亡。从机制上讲，我们发现人皮肤黑色素瘤以及裸鼠肺部mGPDH敲除（ko）转移性异种移植物中的核因子E2相关因子2（NRF2）蛋白水平升高。此外，在A375黑色素瘤细胞中，mGPDH的缺失诱导了NRF2的表达，但不影响NRF2蛋白的降解。另外，在体内和体外，通过进一步下调NRF2可挽救因mGPDH缺失而诱导的黑色素瘤转移。一致地，mGPDH的过表达（oe）抑制了NRF2的表达并减弱了黑色素瘤细胞的恶性特性。总之，我们的研究结果表明，mGPDH通过抑制NRF2和下游氧化信号来抑制黑色素瘤转移，突显了mGPDH在黑色素瘤治疗中的治疗潜力。
Oxidative stress critically influences carcinogenesis and the progression of melanoma, and aggressive malignant melanoma activity is due to its high metastatic ability. Some findings in several cancer cell lines have indicated that mGPDH, a component of the mitochondrial respiratory chain, also modulates oxidative stress. However, the role of mGPDH in melanoma remains elusive. Here, we report that the mGPDH protein level is decreased in human skin melanoma compared to normal skin and decreased in metastatic melanoma compared to primary melanoma. Our in vivo and in vitro experiments indicated that mGPDH depletion accelerated melanoma migration and invasion without affecting proliferation or apoptosis. Mechanistically, we found elevated NRF2 protein levels in human skin melanoma and mGPDH‐knockout (ko) metastatic xenografts in the lungs of nude mice. Moreover, in A375 melanoma cells, the loss of mGPDH‐induced NRF2 expression but did not affect NRF2 protein degradation. Additionally, melanoma metastasis induced by the loss of mGPDH was rescued by the further down‐regulation of NRF2 in vivo and in vitro. Consistently, mGPDH overexpression (oe) depressed NRF2 expression and attenuated the malignant properties of melanoma cells. In conclusion, our findings suggest that mGPDH suppresses melanoma metastasis by inhibiting NRF2 and downstream oxidative signals, highlighting the therapeutic potential of mGPDH for melanoma treatment.
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影响因子：
3.3
作者：
Chowdhury, Subir K. Roy;Raha, Sandeep;Singh, Gurmit
通讯作者：
Singh, Gurmit
影响因子：
64.5
作者：
Lignitto, Luca;LeBoeuf, Sarah E.;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
9
作者：
Khamari R;Trinh A;Gabert PE;Corazao-Rozas P;Riveros-Cruz S;Balayssac S;Malet-Martino M;Dekiouk S;Joncquel Chevalier Curt M;Maboudou P;Garçon G;Ravasi L;Guerreschi P;Mortier L;Quesnel B;Marchetti P;Kluza J
通讯作者：
Kluza J
NRF2 在糖尿病伤口愈合中的重要作用。
影响因子：
7.7
作者：
Long M;Rojo de la Vega M;Wen Q;Bharara M;Jiang T;Zhang R;Zhou S;Wong PK;Wondrak GT;Zheng H;Zhang DD
通讯作者：
Zhang DD
影响因子：
3.1
作者：
Azoury, Said C.;Lange, Julie R.
通讯作者：
Lange, Julie R.