The role of the complement system in the immune mechanism of HCC and its therapeutic perspectives_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Xiaoshen , WANG Zhixin , WANG Hao , DU Lei ,  REN Li

Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qinghai University, Xining 810001, P. R. China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, P. R. China;

Corresponding author：

REN Li, Email: renli_xn@163.com

Keywords：

hepatocellular carcinoma; complement system; immunomodulation; treatments

DOI：

10.7507/1007-9424.202407015

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To understand the role of complement system in the immune mechanism of hepatocellular carcinoma (HCC) and its potential therapeutic value, and to provide reference for related research in the field of HCC immunotherapy. Methods Read and review the national and international literature on hepatocellular carcinoma and complement-related studies. Results A total of eight complement components closely related to HCC were summarized, which play an important role in the immune regulation of HCC, and their activation can be involved in the occurrence and development of HCC through a variety of mechanisms, and their use as complement inhibitors can regulate the activity of complement-related activation pathways and enhance anti-tumor ability, potentially providing a new strategy for the treatment of HCC. Conclusion A variety of complement components in the complement system play an important role in regulating the immune mechanism of HCC, and the activation of the complement system is closely related to the occurrence and development of HCC, which is expected to be a potential immunotherapeutic target for HCC. However, the combination of complement-related inhibitor therapy with other antitumor immunotherapies carries certain risks and benefits, which need to be thoroughly investigated.

1.	Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology, 2023, 77(5): 1773-1796.
2.	郝运, 李川, 文天夫, 等. 全球及中国的肝癌流行病学特征: 基于《2022全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(7): 781-789.
3.	姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
4.	何坤, 高孝锦, 谢梦忆, 等. 着丝粒蛋白家族对肝癌恶性生物学行为调节的研究进展. 中国普外基础与临床杂志, 2024, 31(6): 761-768.
5.	West EE, Woodruff T, Fremeaux-Bacchi V, et al. Complement in human disease: approved and up-and-coming therapeutics. Lancet, 2024, 403(10424): 392-405.
6.	Markiewski MM, DeAngelis RA, Benencia F, et al. Modulation of the antitumor immune response by complement. Nat Immunol, 2008, 9(11): 1225-1235.
7.	Zhang R, Liu Q, Li T, et al. Role of the complement system in the tumor microenvironment. Cancer Cell Int, 2019, 19: 300.
8.	Bandini S, Macagno M, Hysi A, et al. The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis. Oncoimmunology, 2016, 5(12): e1253653. doi: 10.1080/2162402X.2016.1253653.
9.	Bulla R, Tripodo C, Rami D, Ling GS, et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun, 2016, 7: 10346. doi: 10.1038/ncomms10346.
10.	Reis ES, Mastellos DC, Hajishengallis G, et al. New insights into the immune functions of complement. Nat Rev Immunol, 2019, 19(8): 503-516.
11.	Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood, 2019, 133(20): 2159-2167.
12.	He G, Yu GY, Temkin V, et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell, 2010, 17(3): 286-297.
13.	徐令东, 徐逸帆, 张飞, 等. 肝炎病毒感染导致肝细胞癌发生的免疫机制研究进展. 浙江大学学报(医学版), 2024, 53(1): 64-72.
14.	Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol, 2020, 11: 940.
15.	Xing M, Li J. A new inflammation-related risk model for predicting hepatocellular carcinoma prognosis. Biomed Res Int, 2022, 2022: 5396128. doi: 10.1155/2022/5396128.
16.	Xiao Z, Yeung CLS, Yam JWP, et al. An update on the role of complement in hepatocellular carcinoma. Front Immunol, 2022, 13: 1007382. doi: 10.3389/fimmu.2022.1007382.
17.	Herbert A. Complement controls the immune synapse and tumors control complement. J Immunother Cancer, 2020, 8(2): e001712. doi: 10.1136/jitc-2020-001712.
18.	Rutkowski MJ, Sughrue ME, Kane AJ, et al. Cancer and the complement cascade. Mol Cancer Res, 2010, 8(11): 1453-1465.
19.	Arlaud GJ, Gaboriaud C, Thielens NM, et al. Structural biology of C1: dissection of a complex molecular machinery. Immunol Rev, 2001, 180: 136-145.
20.	Yu H, Yan X, Chen G, et al. Dynamic network biomarker C1QTNF1 regulates tumor formation at the tipping point of hepatocellular carcinoma. Biomol Biomed, 2024, 24(4): 939-951.
21.	Wan X, Zheng C, Dong L. Inhibition of CTRP6 prevented survival and migration in hepatocellular carcinoma through inactivating the AKT signaling pathway. J Cell Biochem, 2019, 120(10): 17059-17066.
22.	Lee JH, Poudel B, Ki HH, et al. Complement C1q stimulates the progression of hepatocellular tumor through the activation of discoidin domain receptor 1. Sci Rep, 2018, 8(1): 4908. doi: 10.1038/s41598-018-23240-6.
23.	Ho TC, Wang EY, Yeh KH, et al. Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver. Proc Natl Acad Sci U S A, 2020, 117(12): 6717-6725.
24.	Weber JS, Sznol M, Sullivan RJ, et al. A serum protein signature associated with outcome after anti-PD-1 Therapy in metastatic melanoma. Cancer Immunol Res, 2018, 6(1): 79-86.
25.	Pio R, Ajona D, Lambris JD. Complement inhibition in cancer therapy. Semin Immunol, 2013, 25(1): 54-64.
26.	Chen M, Daha MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun, 2010, 34(3): J276-J286. doi: 10.1016/j.jaut.2009.11.014.
27.	Xu Y, Huang Y, Xu W, et al. Activated hepatic stellate cells (HSCs) exert immunosuppressive effects in hepatocellular carcinoma by producing complement C3. Onco Targets Ther, 2020, 13: 1497-1505.
28.	Hsieh CC, Chou HS, Yang HR, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood, 2013, 121(10): 1760-1768.
29.	Lu LC, Chang CJ, Hsu CH. Targeting myeloid-derived suppressor cells in the treatment of hepatocellular carcinoma: current state and future perspectives. J Hepatocell Carcinoma, 2019, 6: 71-84.
30.	Malik A, Thanekar U, Amarachintha S, et al. “Complimenting the complement”: Mechanistic insights and opportunities for therapeutics in hepatocellular carcinoma. Front Oncol, 2021, 10: 627701. doi: 10.3389/fonc.2020.627701 Ther, 2021, 6(1): 404.
31.	Worthley DL, Bardy PG, Gordon DL, et al. Mannose-binding lectin and maladies of the bowel and liver. World J Gastroenterol, 2006, 12(40): 6420-6428.
32.	Kalia N, Singh J, Kaur M. The ambiguous role of mannose-binding lectin (MBL) in human immunity. Open Med (Wars), 2021, 16(1): 299-310.
33.	Liao H, Yang J, Xu Y, et al. Mannose-binding lectin 2 as a potential therapeutic target for hepatocellular carcinoma: multi-omics analysis and experimental validation. Cancers (Basel), 2023, 15(19): 4900. doi: 10.3390/cancers15194900.
34.	Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol, 2023, 23(2): 90-105.
35.	Su C, Lin Y, Cai L, et al. Association between mannose-binding lectin variants, haplotypes and risk of hepatocellular carcinoma: A case-control study. Sci Rep, 2016, 6: 32147. doi: 10.1038/srep32147.
36.	Li J, Li H, Yu Y, et al. Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway. Oncoimmunology, 2018, 8(2): e1527650. doi: 10.1080/2162402X.2018.1527650.
37.	Laskowski J, Renner B, Pickering MC, et al. Complement factor H-deficient mice develop spontaneous hepatic tumors. J Clin Invest, 2020, 130(8): 4039-4054.
38.	Fan CW, Chen T, Shang YN, et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis, 2013, 4(10): e828. doi: 10.1038/cddis.2013.337.
39.	Liu J, Li W, Zhao H. CFHR3 is a potential novel biomarker for hepatocellular carcinoma. J Cell Biochem, 2020, 121(4): 2970-2980.
40.	Chen E, Zou Z, Wang R, et al. Predictive value of a stemness-based classifier for prognosis and immunotherapy response of hepatocellular carcinoma based on bioinformatics and machine-learning strategies. Front Immunol, 2024, 15: 1244392. doi: 10.3389/fimmu.2024.1244392.
41.	Ruan WY, Zhang L, Lei S, et al. An inflammation-associated ferroptosis signature optimizes the diagnosis, prognosis evaluation and immunotherapy options in hepatocellular carcinoma. J Cell Mol Med, 2023, 27(13): 1820-1835.
42.	Blom AM, Villoutreix BO, Dahlbäck B. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol Immunol, 2004, 40(18): 1333-1346.
43.	Dong W, Xia Z, Chai Z, et al. Proteomic analysis of small extracellular vesicles from the plasma of patients with hepatocellular carcinoma. World J Surg Oncol, 2022, 20(1): 387. doi: 10.1186/s12957-022-02849-y.
44.	Dalal K, Khorate P, Dalal B, et al. Differentially expressed serum host proteins in hepatitis B and C viral infections. Virusdisease, 2018, 29(4): 468-477.
45.	Xu YQ, Gao YD, Yang J, et al. A defect of CD4⁺CD25⁺ regulatory T cells in inducing interleukin-10 production from CD4⁺ T cells under CD46 costimulation in asthma patients. J Asthma, 2010, 47(4): 367-373.
46.	Li X, Wang Q, Ai L, et al. Unraveling the activation process and core driver genes of HSCs during cirrhosis by single-cell transcriptome. Exp Biol Med (Maywood), 2023, 248(16): 1414-1424.
47.	Liu F, Luo L, Liu Z, et al. A genetic variant in the promoter of CD46 is associated with the risk and prognosis of hepatocellular carcinoma. Mol Carcinog, 2020, 59(11): 1243-1255.
48.	Chen W, Wu Y, Liu W, et al. Enhanced antitumor efficacy of a novel fiber chimeric oncolytic adenovirus expressing p53 on hepatocellular carcinoma. Cancer Lett, 2011, 307(1): 93-103.
49.	Meri S, Morgan BP, Davies A, et al. Human protectin (CD59), an 18 000–20 000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology, 1990, 71(1): 1-9.
50.	Fishelson Z, Donin N, Zell S, et al. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol, 2003, 40(2-4): 109-123.
51.	Abdel-Latif M, Saidan S, Morsy BM. Coenzyme Q10 attenuates rat hepatocarcinogenesis via the reduction of CD59 expression and phospholipase D activity. Cell Biochem Funct, 2020, 38(4): 490-499.
52.	Lan T, Wu H. Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma // Philadelphia: Proceedings: AACR Annual Meeting 2020. doi:10.158/1538-7445.AM2020-2932.
53.	Hu WH, Hu Z, Shen X, et al. C5a receptor enhances hepatocellular carcinoma cell invasiveness via activating ERK1/2-mediated epithelial-mesenchymal transition. Exp Mol Pathol, 2016, 100(1): 101-108.
54.	Kolev M, Markiewski MM. Targeting complement-mediated immunoregulation for cancer immunotherapy. Semin Immunol, 2018, 37: 85-97.
55.	Hsu BE, Tabariès S, Johnson RM, et al. Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis. Cell Rep, 2019, 27(13): 3902-3915.
56.	Lin D, Shen L, Luo M, et al. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther, 2021, 6(1): 404. doi: 10.1038/s41392-021-00817-8.
57.	Medler TR, Murugan D, Horton W, et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell, 2018, 34(4): 561-578.
58.	Li Z, Meng X, Wu P, et al. Glioblastoma cell-derived lncRNA-containing exosomes induce microglia to produce complement C5, promoting chemotherapy resistance. Cancer Immunol Res, 2021, 9(12): 1383-1399.
59.	Yang C, Yang F, Chen X, et al. Overexpression of complement C5a indicates poor survival and therapeutic response in metastatic renal cell carcinoma. Int J Biol Markers, 2023, 38(2): 124-132.
60.	Imamura R, Kitagawa S, Kubo T, et al. Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a. Prostate, 2021, 81(3): 147-156.

1. Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology, 2023, 77(5): 1773-1796.
2. 郝运, 李川, 文天夫, 等. 全球及中国的肝癌流行病学特征: 基于《2022全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(7): 781-789.
3. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
4. 何坤, 高孝锦, 谢梦忆, 等. 着丝粒蛋白家族对肝癌恶性生物学行为调节的研究进展. 中国普外基础与临床杂志, 2024, 31(6): 761-768.
5. West EE, Woodruff T, Fremeaux-Bacchi V, et al. Complement in human disease: approved and up-and-coming therapeutics. Lancet, 2024, 403(10424): 392-405.
6. Markiewski MM, DeAngelis RA, Benencia F, et al. Modulation of the antitumor immune response by complement. Nat Immunol, 2008, 9(11): 1225-1235.
7. Zhang R, Liu Q, Li T, et al. Role of the complement system in the tumor microenvironment. Cancer Cell Int, 2019, 19: 300.
8. Bandini S, Macagno M, Hysi A, et al. The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis. Oncoimmunology, 2016, 5(12): e1253653. doi: 10.1080/2162402X.2016.1253653.
9. Bulla R, Tripodo C, Rami D, Ling GS, et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun, 2016, 7: 10346. doi: 10.1038/ncomms10346.
10. Reis ES, Mastellos DC, Hajishengallis G, et al. New insights into the immune functions of complement. Nat Rev Immunol, 2019, 19(8): 503-516.
11. Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood, 2019, 133(20): 2159-2167.
12. He G, Yu GY, Temkin V, et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell, 2010, 17(3): 286-297.
13. 徐令东, 徐逸帆, 张飞, 等. 肝炎病毒感染导致肝细胞癌发生的免疫机制研究进展. 浙江大学学报(医学版), 2024, 53(1): 64-72.
14. Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol, 2020, 11: 940.
15. Xing M, Li J. A new inflammation-related risk model for predicting hepatocellular carcinoma prognosis. Biomed Res Int, 2022, 2022: 5396128. doi: 10.1155/2022/5396128.
16. Xiao Z, Yeung CLS, Yam JWP, et al. An update on the role of complement in hepatocellular carcinoma. Front Immunol, 2022, 13: 1007382. doi: 10.3389/fimmu.2022.1007382.
17. Herbert A. Complement controls the immune synapse and tumors control complement. J Immunother Cancer, 2020, 8(2): e001712. doi: 10.1136/jitc-2020-001712.
18. Rutkowski MJ, Sughrue ME, Kane AJ, et al. Cancer and the complement cascade. Mol Cancer Res, 2010, 8(11): 1453-1465.
19. Arlaud GJ, Gaboriaud C, Thielens NM, et al. Structural biology of C1: dissection of a complex molecular machinery. Immunol Rev, 2001, 180: 136-145.
20. Yu H, Yan X, Chen G, et al. Dynamic network biomarker C1QTNF1 regulates tumor formation at the tipping point of hepatocellular carcinoma. Biomol Biomed, 2024, 24(4): 939-951.
21. Wan X, Zheng C, Dong L. Inhibition of CTRP6 prevented survival and migration in hepatocellular carcinoma through inactivating the AKT signaling pathway. J Cell Biochem, 2019, 120(10): 17059-17066.
22. Lee JH, Poudel B, Ki HH, et al. Complement C1q stimulates the progression of hepatocellular tumor through the activation of discoidin domain receptor 1. Sci Rep, 2018, 8(1): 4908. doi: 10.1038/s41598-018-23240-6.
23. Ho TC, Wang EY, Yeh KH, et al. Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver. Proc Natl Acad Sci U S A, 2020, 117(12): 6717-6725.
24. Weber JS, Sznol M, Sullivan RJ, et al. A serum protein signature associated with outcome after anti-PD-1 Therapy in metastatic melanoma. Cancer Immunol Res, 2018, 6(1): 79-86.
25. Pio R, Ajona D, Lambris JD. Complement inhibition in cancer therapy. Semin Immunol, 2013, 25(1): 54-64.
26. Chen M, Daha MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun, 2010, 34(3): J276-J286. doi: 10.1016/j.jaut.2009.11.014.
27. Xu Y, Huang Y, Xu W, et al. Activated hepatic stellate cells (HSCs) exert immunosuppressive effects in hepatocellular carcinoma by producing complement C3. Onco Targets Ther, 2020, 13: 1497-1505.
28. Hsieh CC, Chou HS, Yang HR, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood, 2013, 121(10): 1760-1768.
29. Lu LC, Chang CJ, Hsu CH. Targeting myeloid-derived suppressor cells in the treatment of hepatocellular carcinoma: current state and future perspectives. J Hepatocell Carcinoma, 2019, 6: 71-84.
30. Malik A, Thanekar U, Amarachintha S, et al. “Complimenting the complement”: Mechanistic insights and opportunities for therapeutics in hepatocellular carcinoma. Front Oncol, 2021, 10: 627701. doi: 10.3389/fonc.2020.627701 Ther, 2021, 6(1): 404.
31. Worthley DL, Bardy PG, Gordon DL, et al. Mannose-binding lectin and maladies of the bowel and liver. World J Gastroenterol, 2006, 12(40): 6420-6428.
32. Kalia N, Singh J, Kaur M. The ambiguous role of mannose-binding lectin (MBL) in human immunity. Open Med (Wars), 2021, 16(1): 299-310.
33. Liao H, Yang J, Xu Y, et al. Mannose-binding lectin 2 as a potential therapeutic target for hepatocellular carcinoma: multi-omics analysis and experimental validation. Cancers (Basel), 2023, 15(19): 4900. doi: 10.3390/cancers15194900.
34. Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol, 2023, 23(2): 90-105.
35. Su C, Lin Y, Cai L, et al. Association between mannose-binding lectin variants, haplotypes and risk of hepatocellular carcinoma: A case-control study. Sci Rep, 2016, 6: 32147. doi: 10.1038/srep32147.
36. Li J, Li H, Yu Y, et al. Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway. Oncoimmunology, 2018, 8(2): e1527650. doi: 10.1080/2162402X.2018.1527650.
37. Laskowski J, Renner B, Pickering MC, et al. Complement factor H-deficient mice develop spontaneous hepatic tumors. J Clin Invest, 2020, 130(8): 4039-4054.
38. Fan CW, Chen T, Shang YN, et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis, 2013, 4(10): e828. doi: 10.1038/cddis.2013.337.
39. Liu J, Li W, Zhao H. CFHR3 is a potential novel biomarker for hepatocellular carcinoma. J Cell Biochem, 2020, 121(4): 2970-2980.
40. Chen E, Zou Z, Wang R, et al. Predictive value of a stemness-based classifier for prognosis and immunotherapy response of hepatocellular carcinoma based on bioinformatics and machine-learning strategies. Front Immunol, 2024, 15: 1244392. doi: 10.3389/fimmu.2024.1244392.
41. Ruan WY, Zhang L, Lei S, et al. An inflammation-associated ferroptosis signature optimizes the diagnosis, prognosis evaluation and immunotherapy options in hepatocellular carcinoma. J Cell Mol Med, 2023, 27(13): 1820-1835.
42. Blom AM, Villoutreix BO, Dahlbäck B. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol Immunol, 2004, 40(18): 1333-1346.
43. Dong W, Xia Z, Chai Z, et al. Proteomic analysis of small extracellular vesicles from the plasma of patients with hepatocellular carcinoma. World J Surg Oncol, 2022, 20(1): 387. doi: 10.1186/s12957-022-02849-y.
44. Dalal K, Khorate P, Dalal B, et al. Differentially expressed serum host proteins in hepatitis B and C viral infections. Virusdisease, 2018, 29(4): 468-477.
45. Xu YQ, Gao YD, Yang J, et al. A defect of CD4⁺CD25⁺ regulatory T cells in inducing interleukin-10 production from CD4⁺ T cells under CD46 costimulation in asthma patients. J Asthma, 2010, 47(4): 367-373.
46. Li X, Wang Q, Ai L, et al. Unraveling the activation process and core driver genes of HSCs during cirrhosis by single-cell transcriptome. Exp Biol Med (Maywood), 2023, 248(16): 1414-1424.
47. Liu F, Luo L, Liu Z, et al. A genetic variant in the promoter of CD46 is associated with the risk and prognosis of hepatocellular carcinoma. Mol Carcinog, 2020, 59(11): 1243-1255.
48. Chen W, Wu Y, Liu W, et al. Enhanced antitumor efficacy of a novel fiber chimeric oncolytic adenovirus expressing p53 on hepatocellular carcinoma. Cancer Lett, 2011, 307(1): 93-103.
49. Meri S, Morgan BP, Davies A, et al. Human protectin (CD59), an 18 000–20 000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology, 1990, 71(1): 1-9.
50. Fishelson Z, Donin N, Zell S, et al. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol, 2003, 40(2-4): 109-123.
51. Abdel-Latif M, Saidan S, Morsy BM. Coenzyme Q10 attenuates rat hepatocarcinogenesis via the reduction of CD59 expression and phospholipase D activity. Cell Biochem Funct, 2020, 38(4): 490-499.
52. Lan T, Wu H. Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma // Philadelphia: Proceedings: AACR Annual Meeting 2020. doi:10.158/1538-7445.AM2020-2932.
53. Hu WH, Hu Z, Shen X, et al. C5a receptor enhances hepatocellular carcinoma cell invasiveness via activating ERK1/2-mediated epithelial-mesenchymal transition. Exp Mol Pathol, 2016, 100(1): 101-108.
54. Kolev M, Markiewski MM. Targeting complement-mediated immunoregulation for cancer immunotherapy. Semin Immunol, 2018, 37: 85-97.
55. Hsu BE, Tabariès S, Johnson RM, et al. Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis. Cell Rep, 2019, 27(13): 3902-3915.
56. Lin D, Shen L, Luo M, et al. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther, 2021, 6(1): 404. doi: 10.1038/s41392-021-00817-8.
57. Medler TR, Murugan D, Horton W, et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell, 2018, 34(4): 561-578.
58. Li Z, Meng X, Wu P, et al. Glioblastoma cell-derived lncRNA-containing exosomes induce microglia to produce complement C5, promoting chemotherapy resistance. Cancer Immunol Res, 2021, 9(12): 1383-1399.
59. Yang C, Yang F, Chen X, et al. Overexpression of complement C5a indicates poor survival and therapeutic response in metastatic renal cell carcinoma. Int J Biol Markers, 2023, 38(2): 124-132.
60. Imamura R, Kitagawa S, Kubo T, et al. Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a. Prostate, 2021, 81(3): 147-156.

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