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Association of the MARCO polymorphism rs6761637 with hepatocellular carcinoma susceptibility and clinical characteristics

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Abstract

Hepatocellular carcinoma (HCC) remains a significant health problem with a substantial genetic predisposition. The liver harbors the largest proportion of macrophages among all the solid organs. There is considerable controversy regarding the relationship between the macrophage receptor with collagenous structure (MARCO) and tumor development and progression. Accordingly, we performed this case–control study to determine whether associations exist between the MARCO single nucleotide polymorphism rs6761637 and HCC susceptibility and clinical characteristics. We successfully genotyped 586 HCC cases and 647 controls using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The overall genotype distribution of rs6761637 was similar in the HCC and control groups (P = 0.143). However, the CT + CC genotypes of rs6761637 were slightly more common in the HCC group among female (P = 0.021), overweight (body mass index ≥ 24 kg/m2, P = 0.003), and nonsmoking (P = 0.022) individuals. The minor C allele carriers had a 1.47-fold increased risk of developing large tumor nodules (P = 0.041). rs6761637 did not affect the recurrence-free or overall survival rate of patients with HCC (P = 0.247 and 0.304, respectively). In conclusion, this is the first report of the association between MARCO genetic variations and HCC risk. These results suggest that the MARCO rs6761637 polymorphism may play a regulatory role in HCC carcinogenesis, but it does not seem to predict prognosis.

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The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53. https://doi.org/10.1002/ijc.31937.

    Article  CAS  PubMed  Google Scholar 

  2. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72(2):250–61. https://doi.org/10.1016/j.jhep.2019.08.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tanaka M, Katayama F, Kato H, Tanaka H, Wang J, Qiao YL, et al. Hepatitis B and C virus infection and hepatocellular carcinoma in China: a review of epidemiology and control measures. J Epidemiol. 2011;21(16):401–16. https://doi.org/10.2188/jea.je20100190.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, et al. Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Heal. 2018;6(5):e555–67. https://doi.org/10.1016/S2214-109X(18)30127-X.

    Article  Google Scholar 

  5. Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616. https://doi.org/10.1038/s41571-018-0073-4.

    Article  PubMed  Google Scholar 

  6. Tang A, Hallouch O, Chernyak V, Kamaya A, Sirlin CB. Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis. Abdom Radiol (NY). 2018;43(1):13–25. https://doi.org/10.1007/s00261-017-1209-1.

    Article  Google Scholar 

  7. Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol. 2016;65(5):1031–42. https://doi.org/10.1016/j.jhep.2016.05.035.

    Article  CAS  PubMed  Google Scholar 

  8. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(15):306–21. https://doi.org/10.1038/nri.2017.11.

    Article  CAS  PubMed  Google Scholar 

  9. Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol. Nature Publishing Group; 2013;13 (13):621–34. https://doi.org/10.1038/nri3515

  10. Sun H, Song J, Weng C, Xu J, Huang M, Huang Q, et al. Association of decreased expression of the macrophage scavenger receptor MARCO with tumor progression and poor prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol. 2017;32(5):1107–14. https://doi.org/10.1111/jgh.13633.

    Article  CAS  PubMed  Google Scholar 

  11. Xiao Y, Chen B, Yang K, Wang Q, Liu P, Gu Y, et al. Down-regulation of MARCO associates with tumor progression in hepatocellular carcinoma. Exp Cell Res. 2019;383(2):111542. https://doi.org/10.1016/j.yexcr.2019.111542.

    Article  CAS  PubMed  Google Scholar 

  12. Malfitano AM, Pisanti S, Napolitano F, Di Somma S, Martinelli R, Portella G. Tumor-associated macrophage status in cancer treatment. Cancers (Basel). 2020;12 (7):1987. 2072–6694/12/7/1987

  13. Georgoudaki A-M, Prokopec KE, Boura VF, Hellqvist E, Sohn S, Östling J, et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 2016;15(9):2000–11. https://doi.org/10.1016/j.celrep.2016.04.084.

    Article  CAS  PubMed  Google Scholar 

  14. Ma MJ, Wang HB, Li H, Yang JH, Yan Y, Xie LP, et al. Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population. PLoS ONE. 2011;6(8):4–9. https://doi.org/10.1371/journal.pone.0024069.

    Article  CAS  Google Scholar 

  15. Sahajpal R, Kandoi G, Dhiman H, Raj S, Scaria V, Bhartiya D, et al. HGV&TB: a comprehensive online resource on human genes and genetic variants associated with tuberculosis. Database (Oxford). 2014;2014:bau112. https://doi.org/10.1093/database/bau112

  16. Novakowski KE, Yap NVL, Yin C, Sakamoto K, Heit B, Golding GB, et al. Human-specific mutations and positively selected sites in MARCO confer functional changes. Mol Biol Evol. 2018;35(2):440–50. https://doi.org/10.1093/molbev/msx298.

    Article  CAS  PubMed  Google Scholar 

  17. Liu F, Li F, Luo L, Yang H, Wei Y, Wang W, et al. Genetic variants in cell death pathway genes and HBV-related hepatocellular carcinoma among a Chinese Han population. Apoptosis. 2017;22(8):1035–47. https://doi.org/10.1007/s10495-017-1385-z.

    Article  CAS  PubMed  Google Scholar 

  18. Kao WY, Chiou YY, Hung HH, Su CW, Chou YH, Huo TI, et al. Younger hepatocellular carcinoma patients have better prognosis after percutaneous radiofrequency ablation therapy. J Clin Gastroenterol. 2012;46(1):62–70. https://doi.org/10.1097/MCG.0b013e31822b36cc.

    Article  PubMed  Google Scholar 

  19. Kim J, Ko ME, Nelson RA, Arrington A, Luu C, Falor AE, et al. Increasing age and survival after orthotopic liver transplantation for patients with hepatocellular cancer. J Am Coll Surg. 2014;218(3):431–8. https://doi.org/10.1016/j.jamcollsurg.2013.12.001.

    Article  PubMed  Google Scholar 

  20. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73. https://doi.org/10.1016/S0140-6736(18)30207-1.

    Article  CAS  PubMed  Google Scholar 

  21. Dragani TA. Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol. 2010;52(2):252–7. https://doi.org/10.1016/j.jhep.2009.11.015.

    Article  CAS  PubMed  Google Scholar 

  22. Tian Z, Hou X, Liu W, Han Z, Wei L. Macrophages and hepatocellular carcinoma. Cell Biosci. 2019;9:79. https://doi.org/10.1186/s13578-019-0342-7

  23. Baqir M, Chen CZ, Martin RJ, Thaikoottathil J, Case SR, Minor MN, et al. Cigarette smoke decreases MARCO expression in macrophages: implication in mycoplasma pneumoniae infection. Respir Med. 2008;102(11):1604–10. https://doi.org/10.1016/j.rmed.2008.05.002.

    Article  PubMed  Google Scholar 

  24. Lee K, Woo J, Kim J, Lee C, Yoo C. Cigarette smoke extract decreased basal and lipopolysaccharide-induced expression of MARCO via degradation of p300. Respirology. 2021;26(1):102–11. https://doi.org/10.1111/resp.13867.

    Article  PubMed  Google Scholar 

  25. Klimcakova E, Roussel B, Kovacova Z, Kovacikova M, Siklova-Vitkova M, Combes M, et al. Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat. Diabetologia. 2011;54(4):876–87. https://doi.org/10.1007/s00125-010-2014-3.

    Article  CAS  PubMed  Google Scholar 

  26. Zheng B, Zhu Y-J, Wang H-Y, Chen L. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. Sci China Life Sci. 2017;60(6):575–84. https://doi.org/10.1007/s11427-016-9043-9.

    Article  CAS  PubMed  Google Scholar 

  27. Huang Y, Ge W, Zhou J, Gao B, Qian X, Wang W. The role of tumor associated macrophages in hepatocellular carcinoma. J Cancer. 2021;12(5):1284–94. https://doi.org/10.7150/jca.51346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019;25(19):2279–93. https://doi.org/10.3748/wjg.v25.i19.2279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qin LX, Tang ZY. The prognostic significance of clinical and pathological features in hepatocellular carcinoma. World J Gastroenterol. 2002;8(2):193–9. https://doi.org/10.3748/wjg.v8.i2.193.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Editage (www.editage.com) for their assistance with English language editing.

Funding

This work was funded with grants from the National Natural Science Foundation of China (grant numbers: 81602910 and 81702002), the Department of Science and Technology of Sichuan Province (grant numbers: 2020YFS0137 and 2019YFS0284), and the Sichuan Provincial Cadre Health Research Project of the Sichuan Provincial Health Commission (grant number: 2020–117).

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Contributions

Bei Cai and Fei Liu designed the study; Zhenzhen Su, Limei Luo, and Fei Liu collected the samples, performed the experiments, and conducted the data management; Zhenzhen Su, Xiaojuan Wu, Bin Wei, and Lu Wang performed the statistical analysis; Zhenzhen Su, Limei Luo, and Bei Cai interpreted the results and wrote the original draft; all authors reviewed the manuscript.

Corresponding authors

Correspondence to Fei Liu or Bei Cai.

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This study complied with the Declaration of Helsinki. We performed the study with prior written informed consent from the patients and the approval of the ethics committee of Sichuan University (2017–264).

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The authors declare no competing interests.

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12026_2022_9271_MOESM1_ESM.tif

Supplementary Fig. 1 Liver MARCO expression levels in healthy subjects according to the GTEx database. GTEx, Genotype-Tissue Expression; TPM, transcripts per million. The median TPM of MARCO in males (n =161) and females (n =65) was 4.223 and 9.588, respectively. Mann-Whitney U test was used for comparison. (TIF 631 KB)

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Su, Z., Luo, L., Wu, X. et al. Association of the MARCO polymorphism rs6761637 with hepatocellular carcinoma susceptibility and clinical characteristics. Immunol Res 70, 400–407 (2022). https://doi.org/10.1007/s12026-022-09271-2

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