The role of disulfidptosis-related genes in the clinical prognosis and immune status of hepatocellular carcinoma

Abstract

Drug resistance and poor prognosis in hepatocellular carcinoma (HCC) underscore the urgent need for novel treatments. Disulfidptosis, a recently identified form of metabolism-related regulated cell death, plays a complex role in anti-tumor immunity; however, its precise function in HCC remains unclear. Understanding the proteins and pathways involved in disulfidptosis and its association with disulfidptosisrelated genes (DRGs) in HCC could reveal innovative therapeutic strategies. This study employs bioinformatics to examine the correlation between DRGs and both clinical prognosis and immune status in HCC patients. Risk models were constructed using univariate Cox and least absolute shrinkage and selection operator regression to identify significant genes, with risk scores correlated to survival outcomes across various patient subtypes. In addition, the analysis explored the association of DRGs with prognosis, immune cell infiltration, enriched functional pathways, and immune checkpoints. The risk model identified six key genes: FLNA, NCKAP1, CD2AP, RPN1, SLC7A11, and CAPKAP. Validation through the receiver operating characteristic curve demonstrated the model's exceptional predictive power. Gene network analysis revealed ten essential genes, three of which (FLNA, CD2AP, and CAPZB) were shared with the risk model. FLNA and CAPZB have previously been linked to therapeutic indicators and pathways in HCC. However, there is a lack of comprehensive data connecting CD2AP to clinical therapy or HCC pathways. These findings highlight the significance of DRGs in HCC prognosis and immune regulation, suggesting that DRGtargeted therapies may offer new avenues for HCC treatment.

Keywords

CD2AP / Disulfidptosis / Hepatocellular carcinoma

Acknowledgments

None.

Funding

None.

Conflict of interest

The authors declare they have no competing interests.

Author contributions

Conceptualization: Shanshan Wang

Investigation: Yang Li

Methodology: Xin Xie

Formal analysis: Moxian Chen

Writing -original draft: Qiang Li

Writing -review & editing: Jiaqian Mo

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

Publicly available datasets were analyzed in this study. Clinical data for 424 patients with HCC were obtained from the TCGA database (https://portal.gdc.cancer.gov/).

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263.doi: 10.3322/caac.21834

[2] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3):209-249.doi: 10.3322/caac.21660

[3] Zheng RS, Chen R, Han BF, et al. Cancer incidence and mortality in China, 2022. Zhonghua Zhong Liu Za Zhi. 2024; 46(3):221-231.doi: 10.3760/cma.j.cn112152-20240119-00035

[4] Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019; 16(10):589-604.doi: 10.1038/s41575-019-0186-y

[5] Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019; 380(15):1450-1462.doi: 10.1056/NEJMra1713263

[6] Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18(8):525-543.doi: 10.1038/s41575-021-00438-0

[7] Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022; 19(3):151-172.doi: 10.1038/s41571-021-00573-2

[8] Liu X, Nie L, Zhang Y, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol. 2023; 25(3):404-414.doi: 10.1038/s41556-023-01091-2

[9] Wang Z, Du X, Lian W, et al. A novel disulfidptosis-associated expression pattern in breast cancer based on machine learning. Front Genet. 2023;14:1193944.doi: 10.3389/fgene.2023.1193944

[10] Li M, Wang J, Zhao Y, et al. Identifying and evaluating a disulfidptosis-related gene signature to predict prognosis in colorectal adenocarcinoma patients. Front Immunol. 2024;15:1344637.doi: 10.3389/fimmu.2024.1344637

[11] Li XM, Liu SP, Li Y, Cai XM, Zhang SB, Xie ZF. Identification of disulfidptosis-related genes with immune infiltration in hepatocellular carcinoma. Heliyon. 2023; 9(8):e18436.doi: 10.1016/j.heliyon.2023.e18436

[12] Wada F, Koga H, Akiba J, et al. High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine. Cancer Sci. 2018; 109(9):2801-2810. doi: 10.1111/cas.13728

[13] Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021; 12(8):599-620.doi: 10.1007/s13238-020-00789-5

[14] Zhu JH, De Mello RA, Yan QL, et al. MiR-139-5p/SLC7A 11 inhibits the proliferation, invasion and metastasis of pancreatic carcinoma via PI3K/Akt signaling pathway. Biochim Biophys Acta Mol Basis Dis. 2020; 1866(6):165747. doi: 10.1016/j.bbadis.2020.165747

[15] Machesky LM. Deadly actin collapse by disulfidptosis. Nat Cell Biol. 2023; 25(3):375-376.doi: 10.1038/s41556-023-01100-4

[16] Zheng P, Zhou C, Ding Y, Duan S. Disulfidptosis: A new target for metabolic cancer therapy. J Exp Clin Cancer Res. 2023; 42(1):103.doi: 10.1186/s13046-023-02675-4

[17] Ji PY, Li ZY, Wang H, Dong JT, Li XJ, Yi HL. Arsenic and sulfur dioxide co-exposure induce renal injury via activation of the NF-κB and caspase signaling pathway. Chemosphere. 2019; 224:280-288.doi: 10.1016/j.chemosphere.2019.02.111

[18] Oduro PK, Zheng X, Wei J, et al. The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B. 2022; 12(1):50-75.doi: 10.1016/j.apsb.2021.05.011

[19] Hu FF, Liu CJ, Liu LL, Zhang Q, Guo AY. Expression profile of immune checkpoint genes and their roles in predicting immunotherapy response. Brief Bioinform. 2021; 22(3):bbaa176.doi: 10.1093/bib/bbaa176

[20] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1):7-33.doi: 10.3322/caac.21708

[21] Tang Y, Zhang Y, Hu X. Identification of potential hub genes related to diagnosis and prognosis of hepatitis B virus-related hepatocellular carcinoma via integrated bioinformatics analysis. Biomed Res Int. 2020;2020:4251761.doi: 10.1155/2020/4251761

[22] Xu K, Zhang Y, Yan Z, et al. Identification of disulfidptosis related subtypes, characterization of tumor microenvironment infiltration, and development of DRG prognostic prediction model in RCC, in which MSH 3 is a key gene during disulfidptosis. Front Immunol. 2023;14:1205250. doi: 10.3389/fimmu.2023.1205250

[23] Zhang C, Zhang X, Dai S, Yang W. Exploring prognosis and therapeutic strategies for HBV-HCC patients based on disulfidptosis-related genes. Front Genet. 2024;15:1522484. doi: 10.3389/fgene.2024.1522484

[24] Ai J, Huang H, Lv X, et al. FLNA and PGK1 are two potential markers for progression in hepatocellular carcinoma. Cell Physiol Biochem. 2011; 27(3-4):207-216.doi: 10.1159/000327946

[25] Patarat R, Riku S, Kunadirek P, et al. The expression of FLNA and CLU in PBMCs as a novel screening marker for hepatocellular carcinoma. Sci Rep. 2021; 11(1):14838.doi: 10.1038/s41598-021-94330-1

[26] Li W, Li M, Liao D, et al. Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma. Oncotarget. 2016; 7(34):55110-55127.doi: 10.18632/oncotarget.10399

[27] Li Y, Xu C, Sun B, Zhong F, Cao M, Yang L. Sema3d restrained hepatocellular carcinoma progression through inactivating Pi3k/Akt signaling via interaction with FLNA. Front Oncol. 2022;12:913498.doi: 10.3389/fonc.2022.913498

[28] Donadon M, Di Tommaso L, Soldani C, et al. Filamin a expression predicts early recurrence of hepatocellular carcinoma after hepatectomy. Liver Int. 2018; 38(2):303-311. doi: 10.1111/liv.13522

[29] Sheng F, Chen KX, Liu J, et al. Chromium (VI) promotes EMT by regulating FLNA in BLCA. Environ Toxicol. 2021; 36(8):1694-1701.doi: 10.1002/tox.23165

[30] Ren Q, You Yu S. CD2-associated protein participates in podocyte apoptosis via PI3K/Akt signaling pathway. J Recept Signal Transduct Res. 2016; 36(3):288-291.doi: 10.3109/10799893.2015.1101137

[31] Xie W, Chen C, Han Z, et al. CD2AP inhibits metastasis in gastric cancer by promoting cellular adhesion and cytoskeleton assembly. Mol Carcinog. 2020; 59(4):339-352. doi: 10.1002/mc.23158

[32] Chen C, Xu J, Zhang JX, et al. CD2AP is a potential prognostic biomarker of renal clear cell carcinoma. Cancer Med. 2024; 13(4):e7055. doi: 10.1002/cam4.7055

[33] Zhang H, Zhang C, Tang H, et al. CD2-associated protein contributes to hepatitis C, virus propagation and steatosis by disrupting insulin signaling. Hepatology. 2018; 68(5):1710-1725.doi: 10.1002/hep.30073