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Cullin-1表达调节因子敲低通过调控mTOR/DEPTOR信号通路抑制肌层浸润性移行细胞癌的恶性进展。

Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway.

作者信息

Wang W, Chen H, Liu Z, Qu P, Lan J, Chen H, Zou L, Qiu J

机构信息

Department of Urology, The Fourth Affiliated Hospital of Nantong University (Yancheng First People's Hospital), Jiangsu 224000, China.

Department of Hematology, The Fourth Affiliated Hospital of Nantong University (Yancheng First People's Hospital), Jiangsu 224000, China.

出版信息

Br J Cancer. 2016 Feb 2;114(3):305-13. doi: 10.1038/bjc.2015.444. Epub 2016 Jan 7.

DOI:10.1038/bjc.2015.444
PMID:26742010
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4742580/
Abstract

BACKGROUND

Regulator of cullins-1 (ROC1) is a key subunit in the cullin-RING ligase (CRL) protein complex. Our previous study indicated that ROC1 was essential for bladder cancer cell survival and that ROC1 knockdown inhibited CRL activity, triggering G2 phase arrest and senescence. However, the role of ROC1 in the malignant progression of bladder cancer remained unknown.

METHODS

ROC1 expression in cancer cells was knocked down by siRNA silencing. The effects of ROC1 silencing were evaluated by in vitro assays for cell migration and by an in vivo mouse metastasis model. Epithelial-mesenchymal transition (EMT) induction was evaluated by immunofluorescence staining and western blotting of EMT-associated proteins. ROC1 expression in human tumours was further evaluated by immunohistochemical analysis.

RESULTS

ROC1 knockdown suppresses bladder cancer cell migration by inhibiting EMT. ROC1 knockdown inhibited EMT by inhibiting mammalian target of rapamycin (mTOR) activity via the accumulation of the mTOR-inhibitory protein DEPTOR, a CRL substrate. DEPTOR knockdown partially rescued ROC1 knockdown-inhibited EMT and the ROC1-induced inhibition of cancer cell migration. Furthermore, in vivo studies using a nude mouse metastasis model confirmed the in vitro data. Finally, tissue microarray analysis of clinical bladder cancer specimens indicated a positive correlation between ROC1 expression and EMT.

CONCLUSIONS

ROC1 has an important role in the malignant progression of bladder cancer via the mTOR/DEPTOR pathway. ROC1 may serve as a novel therapeutic target for the treatment of muscle-invasive transitional cell carcinoma.

摘要

背景

Cullin-1调节因子（ROC1）是Cullin-RING连接酶（CRL）蛋白复合物中的关键亚基。我们之前的研究表明，ROC1对膀胱癌细胞的存活至关重要，敲低ROC1会抑制CRL活性，引发G2期阻滞和衰老。然而，ROC1在膀胱癌恶性进展中的作用仍不清楚。

方法

通过小干扰RNA（siRNA）沉默敲低癌细胞中的ROC1表达。通过体外细胞迁移试验和体内小鼠转移模型评估ROC1沉默的效果。通过免疫荧光染色和EMT相关蛋白的蛋白质印迹法评估上皮-间质转化（EMT）的诱导情况。通过免疫组织化学分析进一步评估人肿瘤中ROC1的表达。

结果

敲低ROC1通过抑制EMT来抑制膀胱癌细胞迁移。敲低ROC1通过CRL底物mTOR抑制蛋白DEPTOR的积累抑制雷帕霉素哺乳动物靶标（mTOR）活性，从而抑制EMT。敲低DEPTOR部分挽救了敲低ROC1所抑制的EMT以及ROC1诱导的癌细胞迁移抑制。此外，使用裸鼠转移模型的体内研究证实了体外数据。最后，对临床膀胱癌标本的组织芯片分析表明ROC1表达与EMT之间呈正相关。

结论

ROC1通过mTOR/DEPTOR途径在膀胱癌的恶性进展中起重要作用。ROC1可能作为治疗肌肉浸润性移行细胞癌的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/fc1766e47952/bjc2015444f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/ad8c26c5b001/bjc2015444f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/716516d5aed7/bjc2015444f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/8c02734b8edc/bjc2015444f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/75e4e4bff3e0/bjc2015444f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/38d3c5645d5f/bjc2015444f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/fc1766e47952/bjc2015444f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/ad8c26c5b001/bjc2015444f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/716516d5aed7/bjc2015444f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/8c02734b8edc/bjc2015444f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/75e4e4bff3e0/bjc2015444f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/38d3c5645d5f/bjc2015444f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10f2/4742580/fc1766e47952/bjc2015444f6.jpg

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