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

doi:10.7150/ijbs.70105



Theranostics

International Journal of Medical Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

Global reach, higher impact

Full Text | PDF

Int J Biol Sci 2022; 18(6):2329-2344. doi:10.7150/ijbs.70105 This issue Cite

Research Paper

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

Wuping Yang^1,2,3*, Kenan Zhang^1,2,3*, Zedan Zhang^1,2,3, Jingcheng Zhou^1,2,3, Lei Li^1,2,3, Yawei Xu^1,2,3, Jianhui Qiu^1,2,3, Lin Cai^1,2,3, Yanqing Gong^1,2,3✉, Kan Gong^1,2,3✉

1. Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.
2. Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.
3. Institute of Urology, Peking University, Beijing 100034, P.R. China.
*These authors contributed equally to this work.

Citation:

Yang W, Zhang K, Zhang Z, Zhou J, Li L, Xu Y, Qiu J, Cai L, Gong Y, Gong K. Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. Int J Biol Sci 2022; 18(6):2329-2344. doi:10.7150/ijbs.70105. https://www.ijbs.com/v18p2329.htm

Other styles

Abstract

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.

Keywords: claudin-10, ATP5O, acetylation, mitochondria dysfunction, NDUFS2

Citation styles

APA

Yang, W., Zhang, K., Zhang, Z., Zhou, J., Li, L., Xu, Y., Qiu, J., Cai, L., Gong, Y., Gong, K. (2022). Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. International Journal of Biological Sciences, 18(6), 2329-2344. https://doi.org/10.7150/ijbs.70105.

ACS

Yang, W.; Zhang, K.; Zhang, Z.; Zhou, J.; Li, L.; Xu, Y.; Qiu, J.; Cai, L.; Gong, Y.; Gong, K. Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. Int. J. Biol. Sci. 2022, 18 (6), 2329-2344. DOI: 10.7150/ijbs.70105.

NLM

CSE

Yang W, Zhang K, Zhang Z, Zhou J, Li L, Xu Y, Qiu J, Cai L, Gong Y, Gong K. 2022. Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. Int J Biol Sci. 18(6):2329-2344.

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.