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Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth fatal malignant tumour type worldwide. However, the exact molecular mechanism involved in HCC progression remains unclear. METHODS: Three pairs of HCC and matched portal vein tumour thrombus (PVTT) tissue samples were analysed by isobaric tags...

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Autores principales: Yao, Bowen, Li, Yazhao, Chen, Tianxiang, Niu, Yongshen, Wang, Yufeng, Yang, Yuanyuan, Wei, Xinyu, Liu, Qingguang, Tu, Kangsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982636/
https://www.ncbi.nlm.nih.gov/pubmed/33784016
http://dx.doi.org/10.1002/ctm2.366
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author Yao, Bowen
Li, Yazhao
Chen, Tianxiang
Niu, Yongshen
Wang, Yufeng
Yang, Yuanyuan
Wei, Xinyu
Liu, Qingguang
Tu, Kangsheng
author_facet Yao, Bowen
Li, Yazhao
Chen, Tianxiang
Niu, Yongshen
Wang, Yufeng
Yang, Yuanyuan
Wei, Xinyu
Liu, Qingguang
Tu, Kangsheng
author_sort Yao, Bowen
collection PubMed
description BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth fatal malignant tumour type worldwide. However, the exact molecular mechanism involved in HCC progression remains unclear. METHODS: Three pairs of HCC and matched portal vein tumour thrombus (PVTT) tissue samples were analysed by isobaric tags for relative and absolute quantification (iTRAQ) assay to investigate the differentially expressed proteins. Real‐time quantitative PCR, immunostaining, and immunoblotting were performed to detect cofilin 1 (CFL1) in HCC and non‐tumour tissues. CCK8 and EdU, and Transwell assays, respectively, determined cell proliferation, migration, and invasion of HCC cells. Further, subcutaneous and tail vein injection were performed in nude mice for investigating HCC growth and lung metastasis in vivo. Regulatory effect of hypoxia‐inducible factor‐1α (HIF‐1α) on CFL1 was confirmed by chromatin immunoprecipitation (ChIP) assay. Finally, interaction between CFL1 and phospholipase D1 (PLD1) was studied using immunoprecipitation (IP) assay. RESULTS: The iTRAQ analysis identified expression of CFL1 to be significantly upregulated in PVTT than in HCC tissues. Increased expression of CFL1 was closely associated with unfavourable clinical features, and was an independent risk predictor of overall survival in HCC patients. The knockdown of CFL1 inhibited cell growth viability, invasiveness, and epithelial‐mesenchymal transformation (EMT) in HCC cells. Furthermore, CFL1 silencing significantly suppressed the growth and lung metastasis of HCC cells in nude mice. Next, HIF‐1α directly regulated CFL1 transcription by binding to the hypoxia‐responsive element (HRE) in the promoter. Moreover, we disclosed the interaction between CFL1 and PLD1 in HCC cells using IP assay. Mechanistically, CFL1 maintained PLD1 expression by repressing ubiquitin‐mediated protein degradation, thereby activating AKT signalling in HCC cells. Notably, the CFL1/PLD1 axis was found mediating the hypoxia‐induced activation of the AKT pathway and EMT. CONCLUSION: The analysis suggests that hypoxia‐induced CFL1 increases the proliferation, migration, invasion, and EMT in HCC by activating the PLD1/AKT pathway.
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spelling pubmed-79826362021-03-25 Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway Yao, Bowen Li, Yazhao Chen, Tianxiang Niu, Yongshen Wang, Yufeng Yang, Yuanyuan Wei, Xinyu Liu, Qingguang Tu, Kangsheng Clin Transl Med Research Articles BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth fatal malignant tumour type worldwide. However, the exact molecular mechanism involved in HCC progression remains unclear. METHODS: Three pairs of HCC and matched portal vein tumour thrombus (PVTT) tissue samples were analysed by isobaric tags for relative and absolute quantification (iTRAQ) assay to investigate the differentially expressed proteins. Real‐time quantitative PCR, immunostaining, and immunoblotting were performed to detect cofilin 1 (CFL1) in HCC and non‐tumour tissues. CCK8 and EdU, and Transwell assays, respectively, determined cell proliferation, migration, and invasion of HCC cells. Further, subcutaneous and tail vein injection were performed in nude mice for investigating HCC growth and lung metastasis in vivo. Regulatory effect of hypoxia‐inducible factor‐1α (HIF‐1α) on CFL1 was confirmed by chromatin immunoprecipitation (ChIP) assay. Finally, interaction between CFL1 and phospholipase D1 (PLD1) was studied using immunoprecipitation (IP) assay. RESULTS: The iTRAQ analysis identified expression of CFL1 to be significantly upregulated in PVTT than in HCC tissues. Increased expression of CFL1 was closely associated with unfavourable clinical features, and was an independent risk predictor of overall survival in HCC patients. The knockdown of CFL1 inhibited cell growth viability, invasiveness, and epithelial‐mesenchymal transformation (EMT) in HCC cells. Furthermore, CFL1 silencing significantly suppressed the growth and lung metastasis of HCC cells in nude mice. Next, HIF‐1α directly regulated CFL1 transcription by binding to the hypoxia‐responsive element (HRE) in the promoter. Moreover, we disclosed the interaction between CFL1 and PLD1 in HCC cells using IP assay. Mechanistically, CFL1 maintained PLD1 expression by repressing ubiquitin‐mediated protein degradation, thereby activating AKT signalling in HCC cells. Notably, the CFL1/PLD1 axis was found mediating the hypoxia‐induced activation of the AKT pathway and EMT. CONCLUSION: The analysis suggests that hypoxia‐induced CFL1 increases the proliferation, migration, invasion, and EMT in HCC by activating the PLD1/AKT pathway. John Wiley and Sons Inc. 2021-03-21 /pmc/articles/PMC7982636/ /pubmed/33784016 http://dx.doi.org/10.1002/ctm2.366 Text en © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Yao, Bowen
Li, Yazhao
Chen, Tianxiang
Niu, Yongshen
Wang, Yufeng
Yang, Yuanyuan
Wei, Xinyu
Liu, Qingguang
Tu, Kangsheng
Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title_full Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title_fullStr Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title_full_unstemmed Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title_short Hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway
title_sort hypoxia‐induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the pld1/akt pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982636/
https://www.ncbi.nlm.nih.gov/pubmed/33784016
http://dx.doi.org/10.1002/ctm2.366
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