대한임상검사과학회지 (Korean Journal of Clinical Laboratory Science)

  • 제55권2호
  • /
  • Pages.105-112
  • /
  • 2023
  • /
  • 1738-3544(pISSN)
  • /
  • 2288-1662(eISSN)
대한임상검사과학회 (Korean Society for Clinical Laboratory Science)
권호 표지
DOI QR코드

DOI QR Code

폐 편평세포암종 내 Leucine-Rich Repeat Kinase 2 암촉진 효과와 Interleukin-10 발현과의 연관성

Correlation of Protumor Effects of Leucine-Rich Repeat Kinase 2 with Interleukin-10 Expression in Lung Squamous Cell Carcinoma

  • 이성원 (상지대학교 보건의료대학 임상병리학과) ;
  • 박상욱 (상지대학교 보건의료대학 임상병리학과)
  • Sung Won LEE (Department of Biomedical Laboratory Science, College of Health and Biomedical Services, Sangji University) ;
  • Sangwook PARK (Department of Biomedical Laboratory Science, College of Health and Biomedical Services, Sangji University)
  • 투고 : 2023.04.06
  • 심사 : 2023.05.18
  • 발행 : 2023.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Leucine-rich repeat kinase 2 (LRRK2)는 파킨슨병과 같은 신경퇴행성 질환의 병태생리학적인 측면에서 중요한 역할을 하는 것으로 알려져 있고 주로 뇌뿐만 아니라 폐에서도 발현된다. 그러나 LRRK2 발현이 폐 편평세포암(lung squamous cell carcinoma, LUSC)과 같은 일반적인 폐암의 아형과 병인성이 있는지는 불분명하다. 본 연구에서는 Kaplan Meier 플로터 생물정보학 온라인 도구를 사용하여 폐 편평세포암종 내에서 LRRK2와의 예후 진단가치를 분석하였다. 폐 편평세포암종 환자는 LRRK2의 발현이 높아지면 더 나쁜 예후를 나타낸다고 알려져 왔다. LRRK2 발현이 높은 환자의 경우 종양 돌연변이 부담, 높은 신항원부하, 더 나쁜 생존율, 성별과 상관관계를 보였다. 더욱이, gene expression profiling interactive analysis 데이터분석에서 높은 LRRK2 발현을 가진 환자에서의 심각한 증상은 항염증성 사이토카인(예, IL-4, IL-10)의 높은 발현에 양의 상관관계를 보였지만 염증성 사이토카인은 상관성이 없었다. 이러한 결과에서 IL-10관련 유전자의 높은 발현은 더 나쁜 예후를 보이는 LRRK2-high 환자들에서 유의미하게 연관성을 보였다. 또한, tumor immunity estimation resource 데이터는 큰포식세포가 LRRK2-high LUSC환자에서 IL-10의 기원세포 중 하나임을 보여주었다. 본 연구를 통해 결과적으로 LRRK2-IL10 축의 가설이 LUSC 환자의 잠재적이 치료 표적과 예후 바이오 마커일 수 있음을 보여주었다.

Leucine-rich repeat kinase 2 (LRRK2) is known to play a crucial role in the pathophysiology of neurodegenerative disorders such as Parkinson's disease. LRRK2 is predominantly expressed in the lung as well as the brain. However, it is unclear whether LRRK2 expression correlates with the pathogenesis of lung squamous cell carcinoma (LUSC). This study analyzes the prognostic significance of LRRK2 in LUSC using the Kaplan-Meier plotter tool. High expression of LRRK2 is known to be associated with a bad prognosis in patients with LUSC. Patients with high LRRK2 expression, tumor mutational burden, high neoantigen load, and even gender correlation reportedly have the worse survival rates. In the gene expression profiling interactive analysis (GEPIA) database, the severity of pathogenesis in LUSC with high LRRK2 expression positively corresponds to a high expression of anti-inflammatory cytokines but not inflammatory cytokines. Similarly, the increased expression of interleukin (IL)10-related genes was shown to be significantly linked in LRRK2-high LUSC patients having a poor prognosis. Moreover, the tumor immune estimation resource (TIMER) database suggests that macrophages are one of the cellular sources of IL10 in LRRK2-high LUSC patients. Collectively, our results demonstrate that the postulated LRRK2-IL10 axis is a potential therapeutic target and prognostic biomarker for LUSC.

키워드

참고문헌

  1. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020;16:97-107. https://doi.org/10.1038/s41582-019-0301-2 
  2. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003;39:889-909. https://doi.org/10.1016/s0896-6273(03)00568-3 
  3. Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol. 2006;59:315-322. https://doi.org/10.1002/ana.20791 
  4. Yang C, Pang J, Xu J, Pan H, Li Y, Zhang H, et al. LRRK2 is a candidate prognostic biomarker for clear cell renal cell carcinoma. Cancer Cell Int. 2021;21:343. https://doi.org/10.1186/s12935-021-02047-y 
  5. Ma Q, Xu Y, Liao H, Cai Y, Xu L, Xiao D, et al. Identification and validation of key genes associated with non-small-cell lung cancer. J Cell Physiol. 2019;234:22742-22752. https://doi.org/10.1002/jcp.28839 
  6. Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, et al. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet. 2011;20:4209-4223. https://doi.org/10.1093/hmg/ddr348 
  7. Lebovitz C, Wretham N, Osooly M, Milne K, Dash T, Thornton S, et al. Loss of Parkinson's susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis. Sci Rep. 2021;11:2097. https://doi.org/10.1038/s41598-021-81639-0 
  8. Tian Y, Lv J, Su Z, Wu T, Li X, Hu X, et al. LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis. Proc Natl Acad Sci U S A. 2021;118:e2106685118. https://doi.org/10.1073/pnas.2106685118 
  9. Chen JW, Dhahbi J. Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods. Sci Rep. 2021;11:13323. https://doi.org/10.1038/s41598-021-92725-8 
  10. Huang T, Li J, Zhang C, Hong Q, Jiang D, Ye M, et al. Distinguishing lung adenocarcinoma from lung squamous cell carcinoma by two hypomethylated and three hypermethylated genes: a meta-analysis. PLoS One. 2016;11:e0149088. https://doi.org/10.1371/journal.pone.0149088 
  11. Faruki H, Mayhew GM, Serody JS, Hayes DN, Perou CM, Lai-Goldman M. Lung adenocarcinoma and squamous cell carcinoma gene expression subtypes demonstrate significant differences in tumor immune landscape. J Thorac Oncol. 2017;12:943-953. https://doi.org/10.1016/j.jtho.2017.03.010 
  12. Ischenko I, Liu J, Petrenko O, Hayman MJ. Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells. Cell Death Differ. 2014;21:1218-1228. https://doi.org/10.1038/cdd.2014.38 
  13. Wang J, Zhou J, Zhou Q, Qi Y, Zhang P, Yan C, et al. Dysregulated Th1 cells in lung squamous cell carcinoma. J Leukoc Biol. 2022;112:1567-1576. https://doi.org/10.1002/JLB.1MA0422-208R 
  14. Hatanaka H, Abe Y, Kamiya T, Morino F, Nagata J, Tokunaga T, et al. Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer. Ann Oncol. 2000;11:815-819. https://doi.org/10.1023/a:1008375208574 
  15. Zeni E, Mazzetti L, Miotto D, Lo Cascio N, Maestrelli P, Querzoli P, et al. Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer. Eur Respir J. 2007;30:627-632. https://doi.org/10.1183/09031936.00129306 
  16. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol. 2011;12:1063-1070. https://doi.org/10.1038/ni.2113 
  17. Thevenet J, Pescini Gobert R, Hooft van Huijsduijnen R, Wiessner C, Sagot YJ. Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS One. 2011;6:e21519. https://doi.org/10.1371/journal.pone.0021519 
  18. Lanczky A, Gyorffy B. Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. J Med Internet Res. 2021;23:e27633. https://doi.org/10.2196/27633 
  19. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98-W102. https://doi.org/10.1093/nar/gkx247 
  20. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77:e108-e110. https://doi.org/10.1158/0008-5472.CAN-17-0307 
  21. Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17:174. https://doi.org/10.1186/s13059-016-1028-7 
  22. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47(D1):D607-D613. https://doi.org/10.1093/nar/gky1131 
  23. Saraiva M, Vieira P, O'Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med. 2020;217:e20190418. https://doi.org/10.1084/jem.20190418 
  24. Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020;877:173090. https://doi.org/10.1016/j.ejphar.2020.173090 
  25. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593-604. https://doi.org/10.1016/j.immuni.2010.05.007 
  26. Cardoso CC, Pereira AC, de Sales Marques C, Moraes MO. Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. Future Microbiol. 2011;6:533-549. https://doi.org/10.2217/fmb.11.39 
  27. Das LM, Binko AM, Traylor ZP, Peng H, Lu KQ. Vitamin D improves sunburns by increasing autophagy in M2 macrophages. Autophagy. 2019;15:813-826. https://doi.org/10.1080/15548627.2019.1569298 
  28. Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, et al. Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm (Vienna). 2011;118:795-808. https://doi.org/10.1007/s00702-011-0653-2 
  29. Ley S, Weigert A, Weichand B, Henke N, Mille-Baker B, Janssen RA, et al. The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages. Oncogene. 2013;32:631-640. https://doi.org/10.1038/onc.2012.77 
  30. Celik MO, Labuz D, Keye J, Glauben R, Machelska H. IL-4 induces M2 macrophages to produce sustained analgesia via opioids. JCI Insight. 2020;5:e133093. https://doi.org/10.1172/jci.insight.133093 
  31. Gessner A, Mohrs K, Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol. 2005;174:1063-1072. https://doi.org/10.4049/jimmunol.174.2.1063 
  32. Rigoni A, Colombo MP, Pucillo C. Mast cells, basophils and eosinophils: from allergy to cancer. Semin Immunol. 2018;35:29-34. https://doi.org/10.1016/j.smim.2018.02.001