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Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma

BACKGROUND: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. METHODS: The effects of FSTL1 on c...

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Autores principales: Liu, Yan, Tan, Xiaojie, Liu, Wenbin, Chen, Xi, Hou, Xiaomei, Shen, Dan, Ding, Yibo, Yin, Jianhua, Wang, Ling, Zhang, Hongwei, Yu, Yongwei, Hou, Jianguo, Thompson, Timothy C., Cao, Guangwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778637/
https://www.ncbi.nlm.nih.gov/pubmed/29357946
http://dx.doi.org/10.1186/s40880-018-0267-2
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author Liu, Yan
Tan, Xiaojie
Liu, Wenbin
Chen, Xi
Hou, Xiaomei
Shen, Dan
Ding, Yibo
Yin, Jianhua
Wang, Ling
Zhang, Hongwei
Yu, Yongwei
Hou, Jianguo
Thompson, Timothy C.
Cao, Guangwen
author_facet Liu, Yan
Tan, Xiaojie
Liu, Wenbin
Chen, Xi
Hou, Xiaomei
Shen, Dan
Ding, Yibo
Yin, Jianhua
Wang, Ling
Zhang, Hongwei
Yu, Yongwei
Hou, Jianguo
Thompson, Timothy C.
Cao, Guangwen
author_sort Liu, Yan
collection PubMed
description BACKGROUND: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. METHODS: The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients. RESULTS: FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118–0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = − 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). CONCLUSIONS: FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.
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spelling pubmed-57786372018-02-05 Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma Liu, Yan Tan, Xiaojie Liu, Wenbin Chen, Xi Hou, Xiaomei Shen, Dan Ding, Yibo Yin, Jianhua Wang, Ling Zhang, Hongwei Yu, Yongwei Hou, Jianguo Thompson, Timothy C. Cao, Guangwen Chin J Cancer Original Article BACKGROUND: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. METHODS: The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients. RESULTS: FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118–0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = − 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). CONCLUSIONS: FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC. BioMed Central 2018-01-22 /pmc/articles/PMC5778637/ /pubmed/29357946 http://dx.doi.org/10.1186/s40880-018-0267-2 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Original Article
Liu, Yan
Tan, Xiaojie
Liu, Wenbin
Chen, Xi
Hou, Xiaomei
Shen, Dan
Ding, Yibo
Yin, Jianhua
Wang, Ling
Zhang, Hongwei
Yu, Yongwei
Hou, Jianguo
Thompson, Timothy C.
Cao, Guangwen
Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title_full Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title_fullStr Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title_full_unstemmed Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title_short Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
title_sort follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778637/
https://www.ncbi.nlm.nih.gov/pubmed/29357946
http://dx.doi.org/10.1186/s40880-018-0267-2
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