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Molecular characteristics associated with ferroptosis in hepatocellular carcinoma progression

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Abstract

The aim of this study was to investigate the genes associated with ferroptosis and the progression of hepatocellular carcinoma (HCC). The RNA sequencing data of erastin-induced ferroptosis in HCC cells were downloaded from the Sequence Read Archive database with accession number SRP119173. The microarray dataset GSE89377 of HCC progression was downloaded from the Gene Expression Omnibus database. The ferroptosis-related genes were screened by differential analysis and HCC progression-related genes were screened by cluster analysis using Mfuzz. Then, the genes associated with ferroptosis and HCC progression were screened by Venn analysis, followed by functional enrichment, protein–protein interaction (PPI) analysis, and transcription factor (TF) prediction. Finally, survival analysis was performed using data from the Cancer Genome Atlas database. A total of 33 upregulated and 52 downregulated genes associated with HCC progression and ferroptosis were obtained, and these genes were significantly involved in the negative regulation of ERK1 and ERK2 cascades; the NAD biosynthetic process; alanine, aspartate, and glutamate metabolism; and other pathways. The PPI network contained 52 genes and 78 interactions, of which, cell division cycle 20 (CDC20) and heat shock protein family B (small) member 1 (HSPB1) were hub genes found in higher degrees. Among the 85 genes associated with HCC progression and ferroptosis, two TFs (activating TF 3 (ATF3) and HLF) were predicted, with HSPB1 targeted by ATF3. In addition, 26 genes that were found to be significantly correlated with the overall survival of HCC patients were screened, including CDC20 and thyroid hormone receptor interactor 13. Several genes associated with HCC progression and ferroptosis were screened based on a comprehensive bioinformatics analysis. These genes played roles in HCC progression and ferroptosis via the negative regulation of the ERK1 and ERK2 cascades; the NAD biosynthetic process; and alanine, aspartate, and glutamate metabolism. ATF3 and HSPB1 played important roles in HCC progression and ferroptosis, with HSPB1 possibly regulated by ATF3.

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Availability of data and materials

The datasets generated during the current study are not publicly available but obtained from corresponding authors on reasonable request.

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Acknowledgements

The authors gratefully acknowledge the database available to us for this study.

Funding

This work was supported by the Zhejiang Medical and Health Technology Projects (No. 2020KY300).

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Authors and Affiliations

  1. Department of Gastroenterology, Huzhou Cent Hospital, Affiliated Cent Hospital HuZhou University, 198 Hongqi Rd, Huzhou, Zhejiang, 313000, People’s Republic of China

    Zuo Fei

  2. Department of Rheumatology, Huzhou Cent Hospital, Affiliated Cent Hospital HuZhou University, 198 Hongqi Rd, Huzhou, Zhejiang, 313000, People’s Republic of China

    Yin Lijuan

  3. Graduate School of Nursing, Huzhou University, No. 1 Bachelor Road, Huzhou, Zhejiang, 313000, China

    Zhuang Jing

  4. Department of Oncology, Huzhou Cent Hospital, Affiliated Cent Hospital Huzhou University, 198 Hongqi Rd, Huzhou, Zhejiang, 313000, People’s Republic of China

    Yang Xi, Pan Yuefen & Han Shuwen

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Contributions

All authors participated in the conception and design of the study; conceived the manuscript: HS and YX; wrote the paper: HS, YX and ZJ; processed the data: YL and ZF; drew figures: ZJ; all authors read and approved the paper.

Corresponding author

Correspondence to Han Shuwen.

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Supplemental Figure 1.

Venn diagram shows the DEGs in chronic hepatitis vs. normal, cirrhosis vs. normal, and HCC vs. normal groups (TIFF 477 kb)

Supplementary material 2 (DOC 36 kb)

Supplemental Table 2.

Obtained clean reads from the SRP119173 dataset (XLS 18 kb)

Supplemental Table 3.

DEGs in erastin vs. control, and in ferrostatin vs. erastin groups (XLS 988 kb)

Supplemental Table 4.

DEGs in chronic hepatitis vs. normal, cirrhosis vs. normal, and HCC vs. normal groups (XLS 610 kb)

Supplemental Table 5.

Upregulated and downregulated HCC progression-related genes (XLS 69 kb)

Supplemental Table 6.

The 26 genes correlated with the prognosis of patients with HCC (XLS 18 kb)

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Fei, Z., Lijuan, Y., Jing, Z. et al. Molecular characteristics associated with ferroptosis in hepatocellular carcinoma progression. Human Cell 34, 177–186 (2021). https://doi.org/10.1007/s13577-020-00431-w

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