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ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling

BACKGROUND: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa...

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Autores principales: Wu, Qi, Zhou, Xiaoqing, Li, Peng, Ding, Mao, You, Shengjie, Xu, Zhaoyu, Ye, Junjie, Chen, Xuedong, Tan, Mingyue, Wang, Jun, Wang, Wei, Qiu, Jianxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106150/
https://www.ncbi.nlm.nih.gov/pubmed/33962660
http://dx.doi.org/10.1186/s13046-021-01935-5
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author Wu, Qi
Zhou, Xiaoqing
Li, Peng
Ding, Mao
You, Shengjie
Xu, Zhaoyu
Ye, Junjie
Chen, Xuedong
Tan, Mingyue
Wang, Jun
Wang, Wei
Qiu, Jianxin
author_facet Wu, Qi
Zhou, Xiaoqing
Li, Peng
Ding, Mao
You, Shengjie
Xu, Zhaoyu
Ye, Junjie
Chen, Xuedong
Tan, Mingyue
Wang, Jun
Wang, Wei
Qiu, Jianxin
author_sort Wu, Qi
collection PubMed
description BACKGROUND: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression. METHODS: The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis. RESULTS: We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis. CONCLUSION: ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01935-5.
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spelling pubmed-81061502021-05-10 ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling Wu, Qi Zhou, Xiaoqing Li, Peng Ding, Mao You, Shengjie Xu, Zhaoyu Ye, Junjie Chen, Xuedong Tan, Mingyue Wang, Jun Wang, Wei Qiu, Jianxin J Exp Clin Cancer Res Research BACKGROUND: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression. METHODS: The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis. RESULTS: We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis. CONCLUSION: ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01935-5. BioMed Central 2021-05-07 /pmc/articles/PMC8106150/ /pubmed/33962660 http://dx.doi.org/10.1186/s13046-021-01935-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wu, Qi
Zhou, Xiaoqing
Li, Peng
Ding, Mao
You, Shengjie
Xu, Zhaoyu
Ye, Junjie
Chen, Xuedong
Tan, Mingyue
Wang, Jun
Wang, Wei
Qiu, Jianxin
ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title_full ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title_fullStr ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title_full_unstemmed ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title_short ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
title_sort roc1 promotes the malignant progression of bladder cancer by regulating p-iκbα/nf-κb signaling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106150/
https://www.ncbi.nlm.nih.gov/pubmed/33962660
http://dx.doi.org/10.1186/s13046-021-01935-5
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