Down-Regulation of Activating Transcription Factor 3 (ATF3) in Hepatoblastoma and Its Relationship with Ferroptosis

Jing-Xiao Li; Jin-Shu Pang; Bin-Tong Yin; Gang Chen; Jun-Hong Chen; Jia-Yuan Luo; Xia Yang; Li-Ting Qin; Jiang-Hui Zeng; Peng Chen; Jia-Bo Chen; Deng Tang

doi:10.2147/IJGM.S340939

Down-Regulation of Activating Transcription Factor 3 (ATF3) in Hepatoblastoma and Its Relationship with Ferroptosis

Int J Gen Med. 2021 Dec 6:14:9401-9418. doi: 10.2147/IJGM.S340939. eCollection 2021.

Authors

Jing-Xiao Li¹, Jin-Shu Pang², Bin-Tong Yin¹, Gang Chen¹, Jun-Hong Chen¹, Jia-Yuan Luo¹, Xia Yang¹, Li-Ting Qin¹, Jiang-Hui Zeng³, Peng Chen⁴, Jia-Bo Chen⁴, Deng Tang¹

Affiliations

¹ Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
² Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
³ Department of Clinical Laboratory, The Third Affiliated Hospital of Guangxi Medical University/Nanning Second People's Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530031, People's Republic of China.
⁴ Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530031, People's Republic of China.

Abstract

Purpose: The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB.

Methods: The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis.

Results: In ten series, the pooled SMD for ATF3 was -0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79-0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related.

Conclusion: The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.

Keywords: ATF3; ferroptosis; hepatoblastoma; transcription factor.

Grants and funding

The present research was supported by the Guangxi Higher Education Undergraduate Teaching Reform Project (2020JGA146, 2021JGA142), the Guangxi Educational Science Planning Key Project (2021B167), the Guangxi Medical High-level Key Talents Training “139” Program (2020), the College Student Innovation and Entrepreneurship Training Program Project (202110598153) and the Guangxi Medical University Future Academic Stars Project (WLXSZX21109).