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

이성원; 박상욱

doi:10.15324/kjcls.2023.55.2.105

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 원문보기

Korean journal of clinical laboratory science : KJCLS = 대한임상검사과학회지, v.55 no.2, 2023년, pp.105 - 112

이성원 (상지대학교 보건의료대학 임상병리학과) , 박상욱 (상지대학교 보건의료대학 임상병리학과)

초록
AI-Helper

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.

Abstract ▼ AI-Helper

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.

주제어

표/그림 (6)

표 Table 1. Clinical characteristics of LUSC patients in Kaplan-Meier Plotter datasets
그림 Figure 1. Correlation of LRRK2 gene to prognosis in LUSC. Using Kaplan-Meier plotter (http://kmplot.com) analysis, mortality rate of LUSC patients with high LRRK2 expression in accordance with (A) progressive stage of tumor, (B) tumor mutation burden, (C) gender, and (D) neoantigen load. Abbreviations: LUSC, lung squamous cell carcinoma; HR, hazard ratio; LRRK2, leucine-rich repeat kinase 2.
그림 Figure 2. Correlation analyses of LRRK2 and anti-inflammatory cytokines in LUSC tumors. Pearson correlation analysis of LRRK2 and inflammatory cytokines gene (IFN-γ, IL-17 ), anti-inflammatory cytokines genes (IL-4, IL-10 ). In this study, GEPIA (http://gepia.cancer-pku.cn/index.html) database was used for analysis. Abbreviations: TPM, transcripts per million reads; LRRK2, leucine-rich repeat kinase 2; LUSC, lung squamous cell carcinoma; IL, interleukin; IFN-γ, interferon gamma; GEPIA, gene expression profiling interactive analysis.
그림 Figure 3. Correlation analyses of LRRK2 and IL10-related gene expression in LUSC tumors. (A) Pearson correlation analysis of LRRK2 and IL10-related gene (NFIL3, NFAT5, NOTCH1, STAT6, MRC1 , PPARG , MAF , BATF , ARG1 , TGFB1 , PRDM1 , AHR , IRF4 , CD36 , VEGFA, JUNB, HIF1A ILRL1, CD163, and PPARGC1A) was conducted in LUSC tumors using the GEPIA (http://gepia. cancer-pku.cn/index.html) tool. (B) Summary of correlation coefficient (R) value from the significant data shown in Figure 3A. Abbreviations: TPM, transcripts per million reads; LRRK2, leucine-rich repeat kinase 2; LUSC, lung squamous cell carcinoma; GEPIA, gene expression profiling interactive analysis.
그림 Figure 4. Protein-protein interactive networks of LRRK2 involving IL-10 related gene expression in LUSC using STRING software. Protein-protein interactive networks of genes (LRRK2, NFIL3, NFAT5, STAT6, MRC1, PPARG, BATF, AHR, IRF4, CD36, JUNB, ILRL1, and CD16) from the significant data shown in Figure 3A was analyzed using STRING software (https://string-db.org/). (A) Confidence networks, (B) evidence networks. Abbreviations: LRRK2, leucine-rich repeat kinase 2; IL, interleukin; LUSC, lung squamous cell carcinoma; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.
그림 Figure 5. A positive correlation of LRRK2 gene expression with infiltration of M2 macrophage in LUSC tumors. The correlation of LRRK2 levels with the infiltration of M1 and M2 macrophages in LUSC tumors was analyzed using TIMER software (https://cistrome.shinyapps.io/timer/). Abbreviations: LRRK2, leucine-rich repeat kinase 2; LUSC, lung squamous cell carcinoma; TIMER, tumor immune estimation resource.

참고문헌 (32)

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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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？

상세보기
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

상세보기

표제어: PCR

동의어: Packet Collision Rate

용어 설명 출처 목록 (6)

용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

연합인증