Abstract
Multiple programmed cell death pathways (pyroptosis, apoptosis, and necroptosis) are closely related to the progression of hepatocellular carcinoma (HCC). Furthermore, molecular interactions among pyroptotic, apoptotic, and necroptotic components may be new targets for cancer therapy. However, the signature of the genes involved in the interaction between pyroptosis, apoptosis, and necroptosis (PANRGs), and their prognostic value, is still unclear in HCC. In this study, we used HCC clinical and expression data from TCGA and GEO to explore the relationship between PANRGs and HCC. First, we determined the copy number variation incidence of 41 PANRGs genes and explored the prognostic correlation of these genes in HCC. Based on PANRGs, two molecular subgroups of HCC associated with prognosis were identified. We also found significant differences in the overall survival time and the immune infiltration of HCC patients between the two subgroups. Finally, based on the nine PANRGs (CDC25B, EZH2, HMOX1, PLK1, SQSTM1, WEE1, TREM2, MYCN, and FLT3), we constructed a prognostic model using LASSO-Cox regression analysis. The prognostic model could predict OS of HCC patients in TCGA and GEO cohorts with high accuracy. Significant correlations were found between prognosis-related PANRGs and the tumor immune microenvironment (TIME), tumor mutational burden (TMB), and drug sensitivity. In conclusion, we explored the role of PANRGs in HCC and the association of these genes with TIME, TMB, and drug sensitivity.
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Data availability
The RNAseq data and simple nucleotide of hepatocellular carcinoma patients that support the findings of this study are available in TCGA (https://portal.gdc.cancer.gov/) and GEO (https://www.ncbi.nlm.nih.gov/geo/) databases. The copy number variation data of HCC patients are available in UCSC Xena (https://xena.ucsc.edu/).
References
Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 1873;1:188314. https://doi.org/10.1016/j.bbcan.2019.188314.
Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: diagnosis, prognosis and treatment response assessment. Cells. 2020;9(6):1370. https://doi.org/10.3390/cells9061370.
Craig AJ, von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A. Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2020;17(3):139–52. https://doi.org/10.1038/s41575-019-0229-4 (Epub 2019 Dec 2 PMID: 31792430).
Woo Y, Lee HJ, Jung YM, Jung YJ. Regulated necrotic cell death in alternative tumor therapeutic strategies. Cells. 2020;9(12):2709. https://doi.org/10.3390/cells9122709.
Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014;147(4):765-783.e4. https://doi.org/10.1053/j.gastro.2014.07.018.
Yan Z, Da Q, Li Z, Lin Q, Yi J, Su Y, Yu G, Ren Q, Liu X, Lin Z, Qu J, Yin W, Liu J. Inhibition of NEK7 suppressed hepatocellular carcinoma progression by mediating cancer cell pyroptosis. Front Oncol. 2022;12: 812655. https://doi.org/10.3389/fonc.2022.812655.
García-Pras E, Fernández-Iglesias A, Gracia-Sancho J, Pérez-Del-Pulgar S. Cell death in hepatocellular carcinoma: pathogenesis and therapeutic opportunities. Cancers (Basel). 2021;14(1):48. https://doi.org/10.3390/cancers14010048.
Heslop KA, Rovini A, Hunt EG, Fang D, Morris ME, Christie CF, Gooz MB, DeHart DN, Dang Y, Lemasters JJ, Maldonado EN. JNK activation and translocation to mitochondria mediates mitochondrial dysfunction and cell death induced by VDAC opening and sorafenib in hepatocarcinoma cells. Biochem Pharmacol. 2020;171:113728. https://doi.org/10.1016/j.bcp.2019.113728.
Wang Y, Kanneganti TD. From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021;19:4641–57. https://doi.org/10.1016/j.csbj.2021.07.038.
Samir P, Malireddi RKS, Kanneganti TD. The PANoptosome: a deadly protein complex driving pyroptosis, apoptosis, and necroptosis (PANoptosis). Front Cell Infect Microbiol. 2020;3(10):238. https://doi.org/10.3389/fcimb.2020.00238.
Identification of pyroptosis-related subtypes, the development of a prognosis model, and characterization of tumor microenvironment infiltration in colorectal cancer.
Predicting the Prognosis of Esophageal Adenocarcinoma by a Pyroptosis-Related Gene Signature.
A Novel Pyroptosis-related Prognostic Model for Hepatocellular Carcinoma.
A prognostic model for hepatocellular carcinoma based on apoptosis-related genes.
Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer.
Identification and Validation a Necroptosis‑related Prognostic Signature and Associated Regulatory Axis in Stomach Adenocarcinoma.
Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for Cox’s proportional hazards model via coordinate descent. J Stat Softw. 2011;39(5):1–13. https://doi.org/10.18637/jss.v039.i05.
Zhao Z, Liu H, Zhou X, Fang D, Ou X, Ye J, Peng J, Xu J. Necroptosis-related lncRNAs: predicting prognosis and the distinction between the cold and hot tumors in gastric cancer. J Oncol. 2021;2021:6718443. https://doi.org/10.1155/2021/6718443.
Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11(2):245–65. https://doi.org/10.1158/2159-8290.CD-20-0789 (Epub 2021 Jan 18 PMID: 33462123).
Moon H, Ro SW. MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel). 2021;13(12):3026. https://doi.org/10.3390/cancers13123026.
Chen Y, Huang Z, Chen X, Ye H. Activation of the toll-like receptor 2 signaling pathway inhibits the proliferation of HCC cells in vitro. Oncol Rep. 2019;42(6):2267–78. https://doi.org/10.3892/or.2019.7340.
Wang J, Zhou Y, Li D, Sun X, Deng Y, Zhao Q. TSPAN31 is a critical regulator on transduction of survival and apoptotic signals in hepatocellular carcinoma cells. FEBS Lett. 2017;591(18):2905–18. https://doi.org/10.1002/1873-3468.12737 (Epub 2017 Sep 7 PMID: 28670683).
Xing X, Chen J, Chen M. Expression of CDC25 phosphatases in human gastric cancer. Dig Dis Sci. 2008;53(4):949–53. https://doi.org/10.1007/s10620-007-9964-4 (Epub 2007 Oct 13 PMID: 17934831).
Kristjánsdóttir K, Rudolph J. Cdc25 phosphatases and cancer. Chem Biol. 2004;11(8):1043–51. https://doi.org/10.1016/j.chembiol.2004.07.007 (PMID: 15324805).
Yan X, Chua MS, He J, So SK. Small interfering RNA targeting CDC25B inhibits liver tumor growth in vitro and in vivo. Mol Cancer. 2008;12(7):19. https://doi.org/10.1186/1476-4598-7-19.
Lou X, Zhu H, Ning L, Li C, Li S, Du H, Zhou X, Xu G. EZH2 regulates intestinal inflammation and necroptosis through the JNK signaling pathway in intestinal epithelial cells. Dig Dis Sci. 2019;64(12):3518–27. https://doi.org/10.1007/s10620-019-05705-4 (Epub 2019 Jul 4 PMID: 31273598).
Yang F, Lv LZ, Cai QC, Jiang Y. Potential roles of EZH2, Bmi-1 and miR-203 in cell proliferation and invasion in hepatocellular carcinoma cell line Hep3B. World J Gastroenterol. 2015;21(47):13268–76. https://doi.org/10.3748/wjg.v21.i47.13268.
Jiang C, He ZL, Hu XH, Ma PY. MiRNA-15a-3p inhibits the metastasis of hepatocellular carcinoma by interacting with HMOX1. Eur Rev Med Pharmacol Sci. 2020;24(24):12694–700. https://doi.org/10.26355/eurrev_202012_24167 (PMID: 33378016).
Wang D, Chang R, Wang G, Hu B, Qiang Y, Chen Z. Polo-like kinase 1-targeting chitosan nanoparticles suppress the progression of hepatocellular carcinoma. Anticancer Agents Med Chem. 2017;17(7):948–54. https://doi.org/10.2174/1871520616666160926111911.
Deeraksa A, Pan J, Sha Y, Liu XD, Eissa NT, Lin SH, Yu-Lee LY. Plk1 is upregulated in androgen-insensitive prostate cancer cells and its inhibition leads to necroptosis. Oncogene. 2013;32(24):2973–83. https://doi.org/10.1038/onc.2012.309.
Zhang H, Zhang Y, Zhu X, Chen C, Zhang C, Xia Y, Zhao Y, Andrisani O, Kong L. DEAD box protein 5 inhibits liver tumorigenesis by stimulating autophagy via interaction with p62/SQSTM1. Hepatology. 2019;69(3):1046–63. https://doi.org/10.1002/hep.30300.
Jiang SP, Li ZR. MiR-503-5p regulates cell epithelial-to-mesenchymal transition, metastasis and prognosis of hepatocellular carcinoma through inhibiting WEE1. Eur Rev Med Pharmacol Sci. 2019;23(5):2028–37. https://doi.org/10.26355/eurrev_201903_17242 (PMID: 30915746).
Tang W, Lv B, Yang B, Chen Y, Yuan F, Ma L, Chen S, Zhang S, Xia J. TREM2 acts as a tumor suppressor in hepatocellular carcinoma by targeting the PI3K/Akt/β-catenin pathway. Oncogenesis. 2019;8(2):9. https://doi.org/10.1038/s41389-018-0115-x.
Qu W, Wang Y, Wu Y, Liu Y, Chen K, Liu X, Zou Z, Huang X, Wu M. Triggering receptors expressed on myeloid cells 2 promotes corneal resistance against pseudomonas aeruginosa by inhibiting caspase-1-dependent pyroptosis. Front Immunol. 2018;25(9):1121. https://doi.org/10.3389/fimmu.2018.01121.
Watanabe S, Suzuki T, Hara F, Yasui T, Uga N, Naoe A, Polyphyllin D. a steroidal saponin in Paris polyphylla, induces apoptosis and necroptosis cell death of neuroblastoma cells. Pediatr Surg Int. 2017;33(6):713–9. https://doi.org/10.1007/s00383-017-4069-4 (Epub 2017 Mar 4 PMID: 28260192).
Yasukawa K, Liew LC, Hagiwara K, Hironaka-Mitsuhashi A, Qin XY, Furutani Y, Tanaka Y, Nakagama H, Kojima S, Kato T, Ochiya T, Gailhouste L. MicroRNA-493-5p-mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion. Cancer Sci. 2020;111(3):869–80. https://doi.org/10.1111/cas.14292.
Sun W, Li SC, Xu L, Zhong W, Wang ZG, Pan CZ, Li J, Jin GZ, Ta N, Dong W, Liu D, Liu H, Wang HY, Ding J. High FLT3 levels may predict sorafenib benefit in hepatocellular carcinoma. Clin Cancer Res. 2020;26(16):4302–12. https://doi.org/10.1158/1078-0432.CCR-19-1858 (Epub 2020 Apr 24 PMID: 32332018).
Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A, Kaley TJ, Kendall SM, Motzer RJ, Hakimi AA, Voss MH, Russo P, Rosenberg J, Iyer G, Bochner BH, Bajorin DF, Al-Ahmadie HA, Chaft JE, Rudin CM, Riely GJ, Baxi S, Ho AL, Wong RJ, Pfister DG, Wolchok JD, Barker CA, Gutin PH, Brennan CW, Tabar V, Mellinghoff IK, DeAngelis LM, Ariyan CE, Lee N, Tap WD, Gounder MM, D’Angelo SP, Saltz L, Stadler ZK, Scher HI, Baselga J, Razavi P, Klebanoff CA, Yaeger R, Segal NH, Ku GY, DeMatteo RP, Ladanyi M, Rizvi NA, Berger MF, Riaz N, Solit DB, Chan TA, Morris LGT. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6. https://doi.org/10.1038/s41588-018-0312-8.
Acknowledgments
This study was funded by the National Key R&D Program of China (2018YFC2000205), Strategic Priority Research Program of Chinese Academy of Sciences (XDB38050200, XDA26040304), National Natural Science Foundation of China (No.61803257) and the Natural Science Foundation of Shanghai (No.18ZR1417200). We acknowledge the TCGA, GEO and STRING databases for free use.
Funding
This work was supported by the National Key R&D Program of China (2018YFC2000205), Strategic Priority Research Program of Chinese Academy of Sciences (XDB38050200, XDA26040304), National Natural Science Foundation of China (No. 61803257) and Natural Science Foundation of Shanghai (No. 18ZR1417200).
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Conception and design of the research: FQ and WK. Acquisition, analysis, and interpretation of data: FQ, WK, SW and KW. Statistical analysis: FQ and KW. Molecular biological analysis: FQ. Drafting the manuscript: FQ. Manuscript revision for important intellectual content: WK. All authors have read and approved the manuscript.
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Qian, F., Kong, W., Wang, S. et al. Predicting the prognosis of hepatocellular carcinoma based on the interaction between pyroptosis, apoptosis, and necroptosis. Clin Exp Med 23, 2087–2104 (2023). https://doi.org/10.1007/s10238-022-00910-4
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DOI: https://doi.org/10.1007/s10238-022-00910-4