Journal
ANNALS OF TRANSLATIONAL MEDICINE
Volume 10, Issue 24, Pages -Publisher
AME PUBLISHING COMPANY
DOI: 10.21037/atm-22-5750
Keywords
Hepatocellular carcinoma (HCC); ferroptosis; post-transcriptional regulation; prognosis; NUDCD1
Categories
Funding
- Nantong Municipal Science and Technology Project [JCZ20119, JCZ21063, JC12022108, MSZ20041]
- scientific research special project of Nantong Health Commission [MS2022059]
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This study identified post-transcriptional regulatory mechanisms and genes related to ferroptosis in hepatocellular carcinoma (HCC). Experimental results showed that loss of NUDCD1 may facilitate ferroptosis in HCC cells.
Background: Ferroptosis is a form of iron-dependent cell death with increased free iron and massive lipid peroxidation. The discovery of ferroptosis offers insights into hepatocellular carcinoma (HCC) treatment. However, post-transcriptional regulation mechanisms of ferroptosis in HCC remain to be elucidated. The present study explored ferroptosis-related genes and their post-transcriptional regulation mechanisms in HCC. Methods: A ferroptosis score was computed in The Cancer Genome Atlas (TCGA) cohort via gene set variation analysis (GSVA), and ferroptosis-related genes were screened by differential expression and correlation analyses. CircRNA/miRNA-mediated ferroptosis-related genes were predicted, and associations of ferroptosis-related genes with m(1)A/m(5)C/m(6)A regulators were analyzed. Immune cell infiltrations were inferred via CIBERSORT. NUDCD1 expression was examined in L-02, SMMC7721, and HepG2 cells via real time quantitative polymerase chain reaction (RT-qPCR) and western blots. After NUDCD1 was silenced, cell viability, glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) expression, and oxidized glutathione/glutathione (GSSG/GSH) and glutathione (GSH) levels were detected in SMMC7721 and HepG2 cells. Results: The ferroptosis score was linked to poor overall survival (OS) of HCC, which was independent of other clinicopathological parameters. Ten ferroptosis-related genes were determined, namely UGT1A6, ATP6V1C1, MAFG, NUDCD1, PPP1R1A, TSKU, CTSB, AIFM2, CTSA, and CTNND2, which were post-transcriptionally regulated by circRNA/miRNA and m(1)A/m(5)C/m(6)A modifications in HCC. Most were significantly linked with most immune cell compositions within the immune microenvironment, and contributed to undesirable clinical outcomes. NUDCD1 was up-regulated in HCC cells, and its loss facilitated the ferroptosis of HCC cells. Conclusions: Overall, our findings determined ferroptosis-related genes post-transcriptionally regulated by circRNA/miRNA and m(1)A/m(5)C/m(6)A RNA modifications, and experiments demonstrated that loss of NUDCD1 may facilitate the ferroptosis of HCC cells, which provides novel insights into the regulatory mechanisms of ferroptosis in HCC.
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