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Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction

Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanis...

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Autores principales: Yang, Wuping, Zhang, Kenan, Zhang, Zedan, Zhou, Jingcheng, Li, Lei, Xu, Yawei, Qiu, Jianhui, Cai, Lin, Gong, Yanqing, Gong, Kan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990465/
https://www.ncbi.nlm.nih.gov/pubmed/35414767
http://dx.doi.org/10.7150/ijbs.70105
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author Yang, Wuping
Zhang, Kenan
Zhang, Zedan
Zhou, Jingcheng
Li, Lei
Xu, Yawei
Qiu, Jianhui
Cai, Lin
Gong, Yanqing
Gong, Kan
author_facet Yang, Wuping
Zhang, Kenan
Zhang, Zedan
Zhou, Jingcheng
Li, Lei
Xu, Yawei
Qiu, Jianhui
Cai, Lin
Gong, Yanqing
Gong, Kan
author_sort Yang, Wuping
collection PubMed
description Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanisms of action remain elusive. During the study, a large number of clinical samples were utilized to verify the reduced expression of CLDN10 in ccRCC and its association with tumor metastasis and poor prognosis, and our results confirmed that lower CLDN10 expression was an independent predictor of shorter OS (HR: 4.0860, 95%CI: 2.4737-6.7490, P<0.0001) and DFS (HR: 4.3680, 95%CI: 2.2800-8.3700, P<0.0001) in metastatic ccRCC patients. CLDN10 overexpression accelerated cell apoptosis and restrained cell proliferation, migration and invasion in vitro. Besides, CLDN10 overexpression suppressed ccRCC growth and lung metastasis and promoted apoptosis in orthotopic models. Mechanistically, we found that CLDN10 overexpression up-regulated the acetylation and expression levels of ATP5O (ATP synthase subunit O, mitochondrial), leading to the dysfunction of mitochondrial, thereby suppressing the growth and metastasis of ccRCC through increasing the levels of NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB and decreasing the levels of N-cadherin and mitochondrial membrane potential. Moreover, knockdown of ATP5O expression based on the overexpression of CLDN10 could reverse the increase in NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB levels, the decrease in N-cadherin and mitochondrial membrane potential levels and the inhibition of ccRCC phenotypes caused by CLDN10 overexpression. Taken together, these findings for the first time illuminate the mechanism by which CLDN10 overexpression suppresses the growth and metastasis of ccRCC.
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spelling pubmed-89904652022-04-11 Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction Yang, Wuping Zhang, Kenan Zhang, Zedan Zhou, Jingcheng Li, Lei Xu, Yawei Qiu, Jianhui Cai, Lin Gong, Yanqing Gong, Kan Int J Biol Sci Research Paper Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanisms of action remain elusive. During the study, a large number of clinical samples were utilized to verify the reduced expression of CLDN10 in ccRCC and its association with tumor metastasis and poor prognosis, and our results confirmed that lower CLDN10 expression was an independent predictor of shorter OS (HR: 4.0860, 95%CI: 2.4737-6.7490, P<0.0001) and DFS (HR: 4.3680, 95%CI: 2.2800-8.3700, P<0.0001) in metastatic ccRCC patients. CLDN10 overexpression accelerated cell apoptosis and restrained cell proliferation, migration and invasion in vitro. Besides, CLDN10 overexpression suppressed ccRCC growth and lung metastasis and promoted apoptosis in orthotopic models. Mechanistically, we found that CLDN10 overexpression up-regulated the acetylation and expression levels of ATP5O (ATP synthase subunit O, mitochondrial), leading to the dysfunction of mitochondrial, thereby suppressing the growth and metastasis of ccRCC through increasing the levels of NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB and decreasing the levels of N-cadherin and mitochondrial membrane potential. Moreover, knockdown of ATP5O expression based on the overexpression of CLDN10 could reverse the increase in NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB levels, the decrease in N-cadherin and mitochondrial membrane potential levels and the inhibition of ccRCC phenotypes caused by CLDN10 overexpression. Taken together, these findings for the first time illuminate the mechanism by which CLDN10 overexpression suppresses the growth and metastasis of ccRCC. Ivyspring International Publisher 2022-03-06 /pmc/articles/PMC8990465/ /pubmed/35414767 http://dx.doi.org/10.7150/ijbs.70105 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Yang, Wuping
Zhang, Kenan
Zhang, Zedan
Zhou, Jingcheng
Li, Lei
Xu, Yawei
Qiu, Jianhui
Cai, Lin
Gong, Yanqing
Gong, Kan
Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title_full Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title_fullStr Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title_full_unstemmed Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title_short Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction
title_sort claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating atp5o and causing mitochondrial dysfunction
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990465/
https://www.ncbi.nlm.nih.gov/pubmed/35414767
http://dx.doi.org/10.7150/ijbs.70105
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