Online first
Research paper
Published online: 2024-06-11

open access

Page views 13
Article views/downloads 8
Get Citation

Connect on Social Media

Connect on Social Media

ARPC3 affects the prognosis for patients with hepatocellular carcinoma by regulating the immune response

Yonghu Song1, Jianhui Li1, Zhenyang Lu1, Yijun Qi1

Abstract

Introduction. Actin related protein 2/3 complex subunit 3 (ARPC3) is associated with a poor prognosis in patients with various cancers. However, the mechanisms by which it affects immunotherapy and prognosis in patients with hepatocellular carcinoma (HCC) remain unclear. 

To explore the effect of ARPC3 on immune checkpoint inhibitors (ICIs), we investigated the association of ARPC3 with immunotherapy-associated ferroptosis genes. 

Material and methods. The expression difference in ARPC3 between normal and HCC tissues and the effect of ARPC3 on prognosis were evaluated by using multiple databases. GSEA was used to predict the pathway by which ARPC3 affects HCC progression. Using the TCGA database, the First Affiliated Hospital of Anhui Medical University (AHMU) database, and the ICGC database, the correlation between ARPC3, tumor-infiltrating lymphocytes (TILs) and immune checkpoints was studied. 

Results. The expression of ARPC3 in normal tissues was lower than that in tumor tissues, and as an independent prognostic risk factor for HCC, patients with HCC whose ARPC3 expression was high had a worse prognosis. GSEA suggested that the upregulation of ARPC3 mainly affected immune-related pathways. Three databases showed that ARPC3 expression levels affected the infiltration levels of B cells, T cells, macrophages, neutrophils, and NK cells in tumors. In addition, we confirmed that ARPC3 may influence the efficacy of ICI therapy by affecting the expression of immune checkpoints and ferroptosis-related genes in HCC. 

Conclusions. ARPC3 is an independent prognostic risk factor for HCC patients and may influence HCC immunotherapy by affecting the expression of immune checkpoints and ferroptosis-related genes.

Article available in PDF format

View PDF Download PDF file

References

  1. Rimassa L, Pressiani T, Merle P, et al. Systemic Treatment Options in Hepatocellular Carcinoma. Liver Cancer. 2019; 8(6): 427–446.
  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.
  3. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014; 63(5): 844–855.
  4. Bruix J, Han KH, Gores G, et al. Liver cancer: Approaching a personalized care. J Hepatol. 2015; 62(1 Suppl): S144–S156.
  5. Wang L, Wang FS. Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges. Hepatol Int. 2019; 13(5): 521–533.
  6. van Kempen LC, Ruiter DJ, van Muijen GNP, et al. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol. 2003; 82(11): 539–548.
  7. Dong H, Yang Y, Gao C, et al. Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype. J Immunother Cancer. 2020; 8(1).
  8. Zhang H, Liu H, Shen Z, et al. Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer. Ann Surg. 2018; 267(2): 311–318.
  9. Zhu H, Wang G, Zhu H, et al. ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors. BMC Cancer. 2021; 21(1): 269.
  10. Kinoshita T, Muramatsu R, Fujita T, et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann Oncol. 2016; 27(11): 2117–2123.
  11. Dieci MV, Radosevic-Robin N, Fineberg S, et al. International Immuno-Oncology Biomarker Working Group on Breast Cancer. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol. 2018; 52(Pt 2): 16–25.
  12. Wang YQ, Chen YP, Zhang Yu, et al. Prognostic significance of tumor-infiltrating lymphocytes in nondisseminated nasopharyngeal carcinoma: A large-scale cohort study. Int J Cancer. 2018; 142(12): 2558–2566.
  13. Kang HJ, Oh JH, Chun SM, et al. Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes. J Hepatol. 2019; 71(1): 91–103.
  14. Pötzsch M, Berg E, Hummel M, et al. Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression. Oncoimmunology. 2020; 9(1): 1824632.
  15. Zhang L, Zhang Y, Lei Y, et al. Proline-rich 11 (PRR11) drives F-actin assembly by recruiting the actin-related protein 2/3 complex in human non-small cell lung carcinoma. J Biol Chem. 2020; 295(16): 5335–5349.
  16. Markwell SM, Ammer AG, Interval ET, et al. Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion. Mol Cancer Res. 2019; 17(4): 987–1001.
  17. Yae K, Keng VW, Koike M, et al. Sleeping beauty transposon-based phenotypic analysis of mice: lack of Arpc3 results in defective trophoblast outgrowth. Mol Cell Biol. 2006; 26(16): 6185–6196.
  18. Mu J, Zhang Y, Hu Y, et al. The role of viral protein Ac34 in nuclear relocation of subunits of the actin-related protein 2/3 complex. Virol Sin. 2016; 31(6): 480–489.
  19. Zhou K, Muroyama A, Underwood J, et al. Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation. Proc Natl Acad Sci U S A. 2013; 110(40): E3820–E3829.
  20. Zhang C, Wu S, Yang XD, et al. Identification of Key Genes for Hepatitis Delta Virus-Related Hepatocellular Carcinoma by Bioinformatics Analysis. Turk J Gastroenterol. 2021; 32(2): 169–177.
  21. Rai A, Greening DW, Xu R, et al. Exosomes Derived from the Human Primary Colorectal Cancer Cell Line SW480 Orchestrate Fibroblast-Led Cancer Invasion. Proteomics. 2020; 20(14): e2000016.
  22. Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 2017; 66(2): 342–351.
  23. Wang Qi, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res. 2021; 399(1): 112453.
  24. Li Bo, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016; 17(1): 174.
  25. Wan PKT, Ryan AJ, Seymour LW. Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus. Mol Ther. 2021; 29(5): 1668–1682.
  26. Hiss S, Eckstein M, Segschneider P, et al. Tumour-Infiltrating Lymphocytes (TILs) and PD-L1 Expression Correlate with Lymph Node Metastasis, High-Grade Transformation and Shorter Metastasis-Free Survival in Patients with Acinic Cell Carcinoma (AciCC) of the Salivary Glands. Cancers (Basel). 2021; 13(5).
  27. Wu J, Gao W, Tang Q, et al. M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring α β Integrin to Tumor Cells. Hepatology. 2021; 73(4): 1365–1380.
  28. He Y, Pei JH, Li XQ, et al. IL-35 promotes EMT through STAT3 activation and induces MET by promoting M2 macrophage polarization in HCC. Biochem Biophys Res Commun. 2021; 559: 35–41.
  29. Wang LP, Lin J, Ma XQ, et al. Exosomal DLX6-AS1 from hepatocellular carcinoma cells induces M2 macrophage polarization to promote migration and invasion in hepatocellular carcinoma through microRNA-15a-5p/CXCL17 axis. J Exp Clin Cancer Res. 2021; 40(1): 177.
  30. Kalathil SG, Wang K, Hutson A, et al. Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. Oncoimmunology. 2020; 9(1): 1824863.
  31. Xu X, Ye L, Zhang Qi, et al. Group‐2 Innate Lymphoid Cells Promote HCC Progression Through CXCL2‐Neutrophil‐Induced Immunosuppression. Hepatology. 2021; 74(5): 2526–2543.
  32. Zhu Q, Pan QZ, Zhong AL, et al. Annexin A3 upregulates the infiltrated neutrophil-lymphocyte ratio to remodel the immune microenvironment in hepatocellular carcinoma. Int Immunopharmacol. 2020; 89(Pt A): 107139.
  33. Sun H, Xu J, Huang Q, et al. Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC. Cancer Res. 2018; 78(23): 6581–6593.
  34. Shin S, Kim M, Lee SJ, et al. Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell-mediated Killing by Regulating Immune-related Genes. Cancer Genomics Proteomics. 2017; 14(5): 349–362.
  35. Tao L, Wang S, Yang L, et al. Reduced Siglec-7 expression on NK cells predicts NK cell dysfunction in primary hepatocellular carcinoma. Clin Exp Immunol. 2020; 201(2): 161–170.
  36. Yan Y, Zheng L, Du Q, et al. Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells. Cancer Immunol Immunother. 2020; 69(9): 1891–1903.
  37. Zhou G, Sprengers D, Boor PPC, et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology. 2017; 153(4): 1107–1119.e10.
  38. Li Y, Xia J, Shao F, et al. Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis. Biochem Biophys Res Commun. 2021; 534: 877–884.
  39. Deng T, Hu B, Jin C, et al. A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma. J Cell Mol Med. 2021; 25(14): 6618–6633.
  40. Qin Z, Xiang C, Zhong F, et al. Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. J Exp Clin Cancer Res. 2019; 38(1): 154.
  41. Abeni E, Salvi A, Marchina E, et al. Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells. Int J Oncol. 2017; 51(1): 128–144.
  42. Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016; 12(8): 1425–1428.
  43. Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020; 66: 89–100.