Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma.
Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma.
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DOI：
10.3389/fonc.2021.783856
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发表时间：
2021
影响因子：
4.7
通讯作者：
Gudas LJ
中科院分区：
文献类型：
--
作者：
Laursen KB;Chen Q;Khani F;Attarwala N;Gross SS;Dow L;Nanus DM;Gudas LJ
线粒体功能障碍和异常糖酵解是人类透明细胞肾癌(CcRCC)的特征。虽然糖酵解得到了深入的研究，但对线粒体在肾小管细胞癌病理中的作用知之甚少。线粒体Ndufa4l2是ccRCC患者生存不良的预测指标，在肾癌细胞系中，该蛋白支持增殖和集落形成。然而，它在ccrccc中的作用仍然是个谜。我们利用我们已建立的名为转基因肾癌(Track)的ccRCC模型，建立了一种新型的基因工程小鼠模型，在该模型中，Dox调控的shRNA表达降低了Ndufa4l2的水平，尤其是在肾近端小管(PT)。这种靶向敲除Ndufa4l2减少了中性肾脏脂质的积累，并与ccRCC标记物碳酸酐酶9(CA9)和烯醇化酶1(ENO1)水平的降低有关。这些发现表明线粒体失调(即高水平的Ndufa4l2)、脂质积累和ccRCC标记物ENO1和CA9的表达之间存在联系，并表明抑制Ndufa4l2可能会减弱脂质积累和ccRCC的发展。
Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.
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影响因子：
3.3
作者：
Krishnan, B;Truong, LD
通讯作者：
Truong, LD
影响因子：
3.2
作者：
MURATA, F;TSUYAMA, S;MURAMATSU, T
通讯作者：
MURAMATSU, T
影响因子：
2.2
作者：
Heidebrecht, F.;Heidebrecht, A.;Bader, A.
通讯作者：
Bader, A.
DOI：
10.1097/01.asn.0000102470.12285.c6
发表时间：
2004-01-01
影响因子：
13.6
作者：
Fiaschi-Taesch, NM;Santos, S;Garcia-Ocaña, A
通讯作者：
Garcia-Ocaña, A
DOI：
10.1111/1440-1681.12768
发表时间：
2017-07-01
影响因子：
2.9
作者：
Li, Jianhua;Bai, Caiyan;Long, Jingning
通讯作者：
Long, Jingning