Cargando…

CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis

BACKGROUND: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. METHODS: Differential expression analysis in...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Xin, Li, Tian-Man, Luo, Jian-Zhu, Lan, Chen-Lu, Wei, Zhong-Liu, Fu, Tian-Hao, Liao, Xi-Wen, Zhu, Guang-Zhi, Ye, Xin-Ping, Peng, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573156/
https://www.ncbi.nlm.nih.gov/pubmed/34765572
http://dx.doi.org/10.2147/JHC.S335425
_version_ 1784595361689501696
author Zhou, Xin
Li, Tian-Man
Luo, Jian-Zhu
Lan, Chen-Lu
Wei, Zhong-Liu
Fu, Tian-Hao
Liao, Xi-Wen
Zhu, Guang-Zhi
Ye, Xin-Ping
Peng, Tao
author_facet Zhou, Xin
Li, Tian-Man
Luo, Jian-Zhu
Lan, Chen-Lu
Wei, Zhong-Liu
Fu, Tian-Hao
Liao, Xi-Wen
Zhu, Guang-Zhi
Ye, Xin-Ping
Peng, Tao
author_sort Zhou, Xin
collection PubMed
description BACKGROUND: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. METHODS: Differential expression analysis in multiple HCC datasets all suggested that CYP2C8 expression was significantly decreased in HCC tissues, compared with para-carcinoma liver tissues. The expression level of CYP2C8 was subsequently compared between HCC tissues and para-carcinoma liver tissues of 70 patients form Guangxi, China, with the result consistent with the above. Survival analysis and ROC analysis indicated that CYP2C8 was equipped with satisfactory diagnostic and prognostic value in HCC. To examine the effect of CYP2C8 on the malignant phenotype of HCC cells, stable transcriptional cell lines with CYP2C8 over-expression were established, and then Cell Counting Kit-8 (CCK8) assay, colony formation assay, cell cycle assay, cell invasion assay and wound healing assay were performed. RESULTS: The results of aforementioned assays suggested that CYP2C8 over-expression restricted the proliferation, clonality, migration, invasion and cell cycle of HCC cells but had no significant effect on cell apoptosis. The enrichment analysis in terms of sequencing data of HCC cell lines with stable CYP2C8 over-expression suggested that CYP2C8 might be related to PI3K/Akt/p27(Kip1) axis. The inhibition of CYP2C8 over-expression on PI3K/Akt/p27(Kip1) axis was subsequently demonstrated with Western blot assay. In the rescue experiment, it was observed that both P27 inhibitor and PI3K agonist counteracted the repressed malignant phenotype caused by CYP2C8 over-expression, which further demonstrated that CYP2C8 played a role in HCC cells via PI3K/Akt/p27(Kip1) axis. DISCUSSION: The results demonstrated that CYP2C8 enhances the anticancer activity of sorafenib in vitro assays and in tumor xenograft model, with Ki-67 down-regulation and PI3K/Akt/p27Kip1 axis inhibition. In conclusion, these findings hinted that CYP2C8 restricted malignant phenotype and sorafenib resistance in HCC via PI3K/Akt/p27(kip1) axis.
format Online
Article
Text
id pubmed-8573156
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Dove
record_format MEDLINE/PubMed
spelling pubmed-85731562021-11-10 CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis Zhou, Xin Li, Tian-Man Luo, Jian-Zhu Lan, Chen-Lu Wei, Zhong-Liu Fu, Tian-Hao Liao, Xi-Wen Zhu, Guang-Zhi Ye, Xin-Ping Peng, Tao J Hepatocell Carcinoma Original Research BACKGROUND: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. METHODS: Differential expression analysis in multiple HCC datasets all suggested that CYP2C8 expression was significantly decreased in HCC tissues, compared with para-carcinoma liver tissues. The expression level of CYP2C8 was subsequently compared between HCC tissues and para-carcinoma liver tissues of 70 patients form Guangxi, China, with the result consistent with the above. Survival analysis and ROC analysis indicated that CYP2C8 was equipped with satisfactory diagnostic and prognostic value in HCC. To examine the effect of CYP2C8 on the malignant phenotype of HCC cells, stable transcriptional cell lines with CYP2C8 over-expression were established, and then Cell Counting Kit-8 (CCK8) assay, colony formation assay, cell cycle assay, cell invasion assay and wound healing assay were performed. RESULTS: The results of aforementioned assays suggested that CYP2C8 over-expression restricted the proliferation, clonality, migration, invasion and cell cycle of HCC cells but had no significant effect on cell apoptosis. The enrichment analysis in terms of sequencing data of HCC cell lines with stable CYP2C8 over-expression suggested that CYP2C8 might be related to PI3K/Akt/p27(Kip1) axis. The inhibition of CYP2C8 over-expression on PI3K/Akt/p27(Kip1) axis was subsequently demonstrated with Western blot assay. In the rescue experiment, it was observed that both P27 inhibitor and PI3K agonist counteracted the repressed malignant phenotype caused by CYP2C8 over-expression, which further demonstrated that CYP2C8 played a role in HCC cells via PI3K/Akt/p27(Kip1) axis. DISCUSSION: The results demonstrated that CYP2C8 enhances the anticancer activity of sorafenib in vitro assays and in tumor xenograft model, with Ki-67 down-regulation and PI3K/Akt/p27Kip1 axis inhibition. In conclusion, these findings hinted that CYP2C8 restricted malignant phenotype and sorafenib resistance in HCC via PI3K/Akt/p27(kip1) axis. Dove 2021-11-03 /pmc/articles/PMC8573156/ /pubmed/34765572 http://dx.doi.org/10.2147/JHC.S335425 Text en © 2021 Zhou et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Zhou, Xin
Li, Tian-Man
Luo, Jian-Zhu
Lan, Chen-Lu
Wei, Zhong-Liu
Fu, Tian-Hao
Liao, Xi-Wen
Zhu, Guang-Zhi
Ye, Xin-Ping
Peng, Tao
CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title_full CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title_fullStr CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title_full_unstemmed CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title_short CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27(kip1) Axis
title_sort cyp2c8 suppress proliferation, migration, invasion and sorafenib resistance of hepatocellular carcinoma via pi3k/akt/p27(kip1) axis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573156/
https://www.ncbi.nlm.nih.gov/pubmed/34765572
http://dx.doi.org/10.2147/JHC.S335425
work_keys_str_mv AT zhouxin cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT litianman cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT luojianzhu cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT lanchenlu cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT weizhongliu cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT futianhao cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT liaoxiwen cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT zhuguangzhi cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT yexinping cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis
AT pengtao cyp2c8suppressproliferationmigrationinvasionandsorafenibresistanceofhepatocellularcarcinomaviapi3kaktp27kip1axis