0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

Abstract DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular re...

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Autores principales:	Caixia Xia, Liyan Shui, Guohua Lou, Bingjue Ye, Wei Zhu, Jing Wang, Shanshan Wu, Xiao Xu, Long Mao, Wanhong Xu, Zhi Chen, Yanning Liu, Min Zheng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/150068b23f294e5daa5fe3ae76c36ef2
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spelling	oai:doaj.org-article:150068b23f294e5daa5fe3ae76c36ef22021-12-02T15:05:30Z0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop10.1038/s41598-017-04487-x2045-2322https://doaj.org/article/150068b23f294e5daa5fe3ae76c36ef22017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04487-xhttps://doaj.org/toc/2045-2322Abstract DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis.Caixia XiaLiyan ShuiGuohua LouBingjue YeWei ZhuJing WangShanshan WuXiao XuLong MaoWanhong XuZhi ChenYanning LiuMin ZhengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Caixia Xia Liyan Shui Guohua Lou Bingjue Ye Wei Zhu Jing Wang Shanshan Wu Xiao Xu Long Mao Wanhong Xu Zhi Chen Yanning Liu Min Zheng 0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
description	Abstract DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis.
format	article
author	Caixia Xia Liyan Shui Guohua Lou Bingjue Ye Wei Zhu Jing Wang Shanshan Wu Xiao Xu Long Mao Wanhong Xu Zhi Chen Yanning Liu Min Zheng
author_facet	Caixia Xia Liyan Shui Guohua Lou Bingjue Ye Wei Zhu Jing Wang Shanshan Wu Xiao Xu Long Mao Wanhong Xu Zhi Chen Yanning Liu Min Zheng
author_sort	Caixia Xia
title	0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
title_short	0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
title_full	0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
title_fullStr	0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
title_full_unstemmed	0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop
title_sort	0404 inhibits hepatocellular carcinoma through a p53/mir-34a/sirt1 positive feedback loop
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/150068b23f294e5daa5fe3ae76c36ef2
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0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

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