利用生物信息学、免疫组化分析肿瘤来源免疫球蛋白在非小细胞肺癌中的表达及临床意义
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摘要
背景与目的经典免疫学理论认为,免疫球蛋白G(immunoglobulinG,IgG)仅由B细胞合成。近年来研究发现恶性肿瘤细胞也可以合成IgG(cancer-IgG)。本研究分析了cancer-IgG在非小细胞肺癌(non-small cell lung cancer, NSCLC)中的表达及临床意义,并初步探究其机制。方法应用数据库分析IgG1重链编码基因(immunoglobulin heavy constant gamma 1, IGHG1)、免疫组化分析cancer-IgG在NSCLC中的表达及与预后的关系;基因富集分析(gene set enrichment analysis, GSEA)方法探究与IGHG1调控相关的信号通路。结果 Cancer-IgG在NSCLC中的表达量显著高于正常组织,与预后呈负相关,并与患者的临床分期(P=0.042)、T分期(P=0.044)和转移(P=0.007)密切相关。GSEA分析显示,IGHG1与细胞黏附、细胞因子相互作用和趋化因子信号通路相关。结论在NSCLC中,cancer-IgG高表达是预后不良的因素,可能与促进肿瘤的侵袭转移相关。
Background and objective It was believed that immunoglobulin G(IgG) was synthesized only by B cells. However, in recent years, researchers have found that a variety of cancer cells can also synthesize IgG(cancer-IgG) which promote the development of tumors. This study analyzed the expression and clinical significance of cancer-IgG in non-small cell lung cancer(NSCLC), and initially explored its mechanism. Methods The expression of IgG1 heavy chain gamma 1(IGHG1) and cancer-IgG were detected by bioinformatics and immunohistochemistry in NSCLC; The gene set enrichment analysis(GSEA) method was used to explore the signaling pathways involved in IGHG1 regulation. Results The expression level of cancer-IgG in NSCLC was significantly higher than that in normal tissues. The high expression group had a poor prognosis and was associated with clinical stage(P=0.042), T stage(P=0.044) and metastasis(P=0.007). GSEA analysis showed that IGHG1 was associated with cell adhesion, cytokine interaction and chemokine signaling pathway. Conclusion High expression of cancer-IgG in NSCLC is a poor prognosis factor, which may be related to the promotion of tumor invasion and metastasis.
Background and objective It was believed that immunoglobulin G(IgG) was synthesized only by B cells. However, in recent years, researchers have found that a variety of cancer cells can also synthesize IgG(cancer-IgG) which promote the development of tumors. This study analyzed the expression and clinical significance of cancer-IgG in non-small cell lung cancer(NSCLC), and initially explored its mechanism. Methods The expression of IgG1 heavy chain gamma 1(IGHG1) and cancer-IgG were detected by bioinformatics and immunohistochemistry in NSCLC; The gene set enrichment analysis(GSEA) method was used to explore the signaling pathways involved in IGHG1 regulation. Results The expression level of cancer-IgG in NSCLC was significantly higher than that in normal tissues. The high expression group had a poor prognosis and was associated with clinical stage(P=0.042), T stage(P=0.044) and metastasis(P=0.007). GSEA analysis showed that IGHG1 was associated with cell adhesion, cytokine interaction and chemokine signaling pathway. Conclusion High expression of cancer-IgG in NSCLC is a poor prognosis factor, which may be related to the promotion of tumor invasion and metastasis.
引文
1 Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin, 2018, 68(6):394-424. doi:10.3322/caac.21492
2 Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin, 2016,66 (4):271-289. doi:10.3322/caac.21349
3 Qiu X, Zhu X, Zhang L, et al. Human epithelial cancers secrete immunoglobulin g with unidentified specificity to promote growth and survival of tumor cells. Cancer Res,2003, 63(19):6488-6495.
4 Liao QY, Liu W, Liu Y, et al. Aberrant high expression of immunoglobulin G in epithelial stem/progenitor-like cells contributes to tumor initiation and metastasis. Oncotarget,2015, 6(37):40081-40094. doi:10.18632/oncotarget.5542
5 Liu Y, Liu D, Wang C, et al. Binding of the monoclonal antibody RP215 to immunoglobulin G in metastatic lung adenocarcinomas is correlated with poor prognosis.Histopathology, 2015, 67(5):645-653. doi:10.1111/his.12686
6 Sheng Z, Liu Y, Qin C, et al. IgG is involved in the migration and invasion of clear cell renal cell carcinoma. J Clin Pathol, 2016, 69(6):497-504. doi:10.1136/jclinpath-2015-202881
7 Sheng Z, Liu Y, Qin C, et al. Involvement of cancerderived IgG in the proliferation, migration and invasion of bladder cancer cells. Oncol Lett, 2016, 12(6):5113-5121.doi:10.3892/ol.2016.5350
8 Lv WQ, Peng J, Wang HC, et al. Expression of cancer cellderived IgG and extra domain A-containing fibronectin in salivary adenoid cystic carcinoma. Arch Oral Biol, 2017,81 :15-20. doi:10.1016/j.archoralbio.2017.04.010
9 Tang JS, Zhang JX, Liu Y, et al. Lung squamous cel l carcinoma cells express non-canonically glycosylated IgG that activates integrin-FAK signaling. Cancer Letters,2018, 430:148-159. doi:10.1016/j.canlet.2018.05.024
10 Lee G, Laflamme E, Chien CH, et al. Molecular identity of a pan cancer marker, CA215. Cancer Biol Ther, 2008,7(12):2007-2014.
11 Chen Z, Gu J. Immunoglobulin G expression in carcinomas and cancer cell lines. Faseb J, 2007, 21(11):2931-2938.doi:10.1096/fj.07-8073com
12 Li X, Ni R, Chen J, et al. The presence of IGHG1 in human pancreatic carcinomas is associated with immune evasion mechanisms. Pancreas, 2011, 40(5):753-761. doi:10.1097/MPA.0b013e318213d51b
13 Liu Y, Chen Z, Niu N, et al. IgG gene expression and its possible significance in prostate cancers. Prostate, 2012,72 (6):690-701. doi:10.1002/pros.21476
14 Niu N, Zhang J, Huang T, et al. IgG expression in human co lorectal cancer and its relationship to cancer cell behaviors. PLoS One, 2012, 7(11):e47362. doi:10.1371/journal.pone.0047362
15 Gu J, Lei Y, Huang Y, et al. Fab fragment glycosylated IgG may play a central role in placental immune evasion.Hum Reprod, 2015, 30(2):380-391. doi:10.1093/humrep/deu323
16 Rousseaux S, Debernardi A, Jacquiau B, et al. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med,2013, 5(186):186ra166. doi:10.1126/scitranslmed.3005723
17 Botling J, Edlund K, Lohr M, et al. Biomarker discovery in non-small cell lung cancer:integrating gene expression profiling, meta-analysis, and tissue microarray validation.Clin Cancer Res, 2013, 19(1):194-204. doi:10.1158/1078-0432.CCR-12-1139
18 Tang Z, Li C, Kang B, et al. GEPIA:a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 2017, 45(W1):W98-W102. doi:10.1093/nar/gkx247
19 Gyorffy B, Surowiak P, Budczies J, et al. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One, 2013, 8(12):e82241. doi:10.1371/journal.pone.0082241
20 Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis:a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005, 102(43):15545-15550. doi:10 .1073/pnas.0506580102
21 Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol, 2006, 6(10):728-740 . doi:10.1038/nri1939
22 Market E, Papavasiliou FN. V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol,2003, 1(1):E16. doi:10.1371/journal.pbio.0000016
23 Zheng H, Li M, Ren W, et al. Expression and secretion of immunoglobulin alpha heavy chain with diverse VDJ recombinations by human epithelial cancer cells. Mol Immunol, 2007, 44(9):2221-2227. doi:10.1016/j.molimm.2006.11.010
24 Xin M, Dong XW, Guo X L. Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis. Biomed Pharmacother, 2015, 69:179-185. doi:10 .1016/j.biopha.2014.11.024
25 Francavilla C, Maddaluno L, Cavallaro U. The functional role of cell adhesion molecules in tumor angiogenesis.Semin Cancer Biol, 2009, 19(5):298-309. doi:10.1016/j.semcancer.2009.05.004
26 He X, Ding X, Wen D, et al. Exploration of the pathways and interaction network involved in bladder cancer cell line with knockdown of Opa interacting protein 5. Pathol Res Pract, 2017, 213(9):1059-1066. doi:10.1016/j.prp.2017.07.029
27 Kim GE, Kim NI, Lee JS, et al. Differentially expressed genes in matched normal, cancer, and lymph node metastases predict clinical outcomes in patients with breast cancer. Appl Immunohistochem Mol Morphol, 2018.[epub ahead of print] doi:10.1097/PAI.0000000000000717
2 Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin, 2016,66 (4):271-289. doi:10.3322/caac.21349
3 Qiu X, Zhu X, Zhang L, et al. Human epithelial cancers secrete immunoglobulin g with unidentified specificity to promote growth and survival of tumor cells. Cancer Res,2003, 63(19):6488-6495.
4 Liao QY, Liu W, Liu Y, et al. Aberrant high expression of immunoglobulin G in epithelial stem/progenitor-like cells contributes to tumor initiation and metastasis. Oncotarget,2015, 6(37):40081-40094. doi:10.18632/oncotarget.5542
5 Liu Y, Liu D, Wang C, et al. Binding of the monoclonal antibody RP215 to immunoglobulin G in metastatic lung adenocarcinomas is correlated with poor prognosis.Histopathology, 2015, 67(5):645-653. doi:10.1111/his.12686
6 Sheng Z, Liu Y, Qin C, et al. IgG is involved in the migration and invasion of clear cell renal cell carcinoma. J Clin Pathol, 2016, 69(6):497-504. doi:10.1136/jclinpath-2015-202881
7 Sheng Z, Liu Y, Qin C, et al. Involvement of cancerderived IgG in the proliferation, migration and invasion of bladder cancer cells. Oncol Lett, 2016, 12(6):5113-5121.doi:10.3892/ol.2016.5350
8 Lv WQ, Peng J, Wang HC, et al. Expression of cancer cellderived IgG and extra domain A-containing fibronectin in salivary adenoid cystic carcinoma. Arch Oral Biol, 2017,81 :15-20. doi:10.1016/j.archoralbio.2017.04.010
9 Tang JS, Zhang JX, Liu Y, et al. Lung squamous cel l carcinoma cells express non-canonically glycosylated IgG that activates integrin-FAK signaling. Cancer Letters,2018, 430:148-159. doi:10.1016/j.canlet.2018.05.024
10 Lee G, Laflamme E, Chien CH, et al. Molecular identity of a pan cancer marker, CA215. Cancer Biol Ther, 2008,7(12):2007-2014.
11 Chen Z, Gu J. Immunoglobulin G expression in carcinomas and cancer cell lines. Faseb J, 2007, 21(11):2931-2938.doi:10.1096/fj.07-8073com
12 Li X, Ni R, Chen J, et al. The presence of IGHG1 in human pancreatic carcinomas is associated with immune evasion mechanisms. Pancreas, 2011, 40(5):753-761. doi:10.1097/MPA.0b013e318213d51b
13 Liu Y, Chen Z, Niu N, et al. IgG gene expression and its possible significance in prostate cancers. Prostate, 2012,72 (6):690-701. doi:10.1002/pros.21476
14 Niu N, Zhang J, Huang T, et al. IgG expression in human co lorectal cancer and its relationship to cancer cell behaviors. PLoS One, 2012, 7(11):e47362. doi:10.1371/journal.pone.0047362
15 Gu J, Lei Y, Huang Y, et al. Fab fragment glycosylated IgG may play a central role in placental immune evasion.Hum Reprod, 2015, 30(2):380-391. doi:10.1093/humrep/deu323
16 Rousseaux S, Debernardi A, Jacquiau B, et al. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med,2013, 5(186):186ra166. doi:10.1126/scitranslmed.3005723
17 Botling J, Edlund K, Lohr M, et al. Biomarker discovery in non-small cell lung cancer:integrating gene expression profiling, meta-analysis, and tissue microarray validation.Clin Cancer Res, 2013, 19(1):194-204. doi:10.1158/1078-0432.CCR-12-1139
18 Tang Z, Li C, Kang B, et al. GEPIA:a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 2017, 45(W1):W98-W102. doi:10.1093/nar/gkx247
19 Gyorffy B, Surowiak P, Budczies J, et al. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One, 2013, 8(12):e82241. doi:10.1371/journal.pone.0082241
20 Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis:a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005, 102(43):15545-15550. doi:10 .1073/pnas.0506580102
21 Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol, 2006, 6(10):728-740 . doi:10.1038/nri1939
22 Market E, Papavasiliou FN. V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol,2003, 1(1):E16. doi:10.1371/journal.pbio.0000016
23 Zheng H, Li M, Ren W, et al. Expression and secretion of immunoglobulin alpha heavy chain with diverse VDJ recombinations by human epithelial cancer cells. Mol Immunol, 2007, 44(9):2221-2227. doi:10.1016/j.molimm.2006.11.010
24 Xin M, Dong XW, Guo X L. Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis. Biomed Pharmacother, 2015, 69:179-185. doi:10 .1016/j.biopha.2014.11.024
25 Francavilla C, Maddaluno L, Cavallaro U. The functional role of cell adhesion molecules in tumor angiogenesis.Semin Cancer Biol, 2009, 19(5):298-309. doi:10.1016/j.semcancer.2009.05.004
26 He X, Ding X, Wen D, et al. Exploration of the pathways and interaction network involved in bladder cancer cell line with knockdown of Opa interacting protein 5. Pathol Res Pract, 2017, 213(9):1059-1066. doi:10.1016/j.prp.2017.07.029
27 Kim GE, Kim NI, Lee JS, et al. Differentially expressed genes in matched normal, cancer, and lymph node metastases predict clinical outcomes in patients with breast cancer. Appl Immunohistochem Mol Morphol, 2018.[epub ahead of print] doi:10.1097/PAI.0000000000000717