Correlation between expression of ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 and programmed cell death-ligand 1 in non-small cell lung cancer
-
摘要:目的
探讨非小细胞肺癌（NSCLC）中卵巢肿瘤泛素异肽酶1（OTUB1）与程序性死亡受体-1配体（PD-L1）的相关性。
方法分析肿瘤基因组数据库（TCGA）中NSCLC与癌旁正常组织OTUB1 mRNA的差异性。基于基因表达谱数据动态分析（GEPIA）探讨NSCLC中OTUB1与PD-L1 mRNA表达相关性。免疫组化法检测46例NSCLC及41例癌旁正常组织蜡块OTUB1及PD-L1蛋白表达，收集临床病例数据及随访资料。分析OTUB1在癌组织与癌旁组织中的表达差异，OTUB1与PD-L1相关性、临床病理特征的关系以及无复发生存期（RFS）预测意义。
结果NSCLC与癌旁正常组织的OTUB1 mRNA及蛋白表达差异均有统计学意义（P < 0.05）。NSCLC的OTUB1与PD-L1 mRNA无相关性（P>0.05），但两者蛋白表达有相关性（P=0.029）。OTUB1与TNM分期有相关性（P=0.039），与年龄、吸烟史、分化程度、转移淋巴结数及病理类型无相关性（P>0.05）。Kaplan-Meier分析显示，TNM分期（P < 0.001）、转移淋巴结数（P=0.001）及分化程度（P=0.042）是RFS的影响因素；OTUB1阴性及阳性中位RFS分别是18、19个月，差异无统计学意义（P>0.05）。COX多因素分析结果提示，分化程度（P=0.005）及TNM分期（P=0.006）是影响RFS的独立危险因素。
结论NSCLC中OTUB1 mRNA及蛋白表达均高于癌旁正常组织。在蛋白水平方面，OTUB1与PD-L1呈正相关。OTUB1表达与TNM分期相关。
-
关键词:
- 非小细胞肺癌 /
- 卵巢肿瘤泛素异肽酶1 /
- 程序性死亡受体-1配体 /
- 免疫治疗 /
- 相关性
Abstract:ObjectiveTo explore the correlation between ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) and programmed cell death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC).
MethodsDifferences of OTUB1 mRNA between NSCLC and corresponding non-tumor normal tissues in the Cancer Genome Atlas (TCGA) were analyzed. The correlation on mRNA expression between OTUB1 and PD-L1 in NSCLC in Gene Expression Profiling Interactive Analysis (GEPIA) was discussed. The protein expressions of OTUB1 and PD-L1 in 46 cases of NSCLC and 41 cases of corresponding non-tumor normal tissues were detected by immunohistochemistry, and the clinical case data and follow-up data were collected. The expression difference of OTUB1 between cancer tissues and adjacent tissues, the correlations between OTUB1 and PD-L1 as well as clinicopathological features, and the predictive significance for recurrence free survival (RFS) were analyzed.
ResultsThere were significant differences in mRNA and protein expressions of OTUB1 between NSCLC and corresponding non-tumor normal tissues (P < 0.05). There was no correlation in mRNA expression between OTUB1 and PD-L1 in NSCLC tissues (P>0.05), but there was a correlation in protein expression between OTUB1 and PD-L1 (P=0.029). OTUB1 was correlated with TNM staging (P=0.039), but had no correlation with age, history of smoking, degree of differentiation, number of metastatic lymph nodes and pathological type (P>0.05). Kaplan-Meier analysis showed that TNM staging (P < 0.001), the number of metastatic lymph nodes (P=0.001) and the degree of differentiation (P=0.042)were the influencing factors of RFS. The median RFS of negative and positive OTUB1 were 18 months and 19 months, respectively, and there was no significant difference (P>0.05). COX multivariate analysis showed that the degree of differentiation (P=0.005) and TNM staging (P=0.006) were the independent risk factors for RFS.
ConclusionThe mRNA and protein expression levels of OTUB1 in NSCLC tissue are higher than those in corresponding non-tumor normal tissues. In terms of protein level, OTUB1 is positively correlated with PD-L1. OTUB1 expression is related to TNM staging.
-
-
![]()
图 1 NSCLC组织与癌旁正常组织中OTUB1 mRNA比较
A: TCGA数据库中LUAD及癌旁正常组织OTUB1 mRNA比较; B: TCGA数据库中LUSC及癌旁正常组织OTUB1 mRNA比较。
表 1 NSCLC组织中OTUB1表达与各临床特征的关系
临床特征 OTUB1 χ2 P 阴性(n=18) 阳性(n=28) 年龄 < 60岁 6 11 0.167 0.683 ≥60岁 12 17 吸烟史 无 8 12 0.011 0.916 有 10 16 分化程度 高分化 6 9 0.007 0.933 中低分化 12 19 转移淋巴结个数 < 3个 15 18 1.961 0.161 ≥3个 3 10 TNM分期 Ⅰ~Ⅱ期 15 15 4.278 0.039 Ⅲ期 3 13 病理类型 腺癌 11 13 0.947 0.331 鳞癌 7 15 
下载: 导出CSV
表 2 NSCLC患者术后RFS的影响因素分析(Kaplan-Meier法)
临床特征 RFS/个月 χ2 P 中位数 95%CI TNM分期 Ⅰ~Ⅱ期 23 10.765~35.235 16.487 <.001 Ⅲ期 10 7.387~12.613 转移淋巴结个数 < 3个 23 17.637~28.363 10.367 0.001 ≥3个 10 7.651~12.349 分化程度 高分化 23 16.098~29.902 4.132 0.042 中低分化 15 10.637~19.363 OTUB1 阴性 18 11.802~24.198 0.323 0.570 阳性 19 10.261~27.739
下载: 导出CSV
-
[1] BARTA J A, POWELL C A, WISNIVESKY J P. Global epidemiology of lung cancer[J]. Ann Glob Heal, 2019, 85(1): 8. doi: 10.5334/aogh.2419
[2] OSMANI L, ASKIN F, GABRIELSON E, et al. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy[J]. Semin Cancer Biol, 2018, 52(pt 1): 103-109. http://www.ncbi.nlm.nih.gov/pubmed/29183778
[3] ZOU W, WOLCHOK J D, CHEN L. PD-L1(B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations[J]. Sci Transl Med, 2016, 8(328): 328rv4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859220/pdf/nihms-780239.pdf
[4] EIKAWA S, NISHIDA M, MIZUKAMI S, et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin[J]. PNAS, 2015, 112(6): 1809-1814. doi: 10.1073/pnas.1417636112
[5] YANG Y, HSU J M, SUN L, et al. Palmitoylation stabilizes PD-L1 to promote breast tumor growth[J]. Cell Res, 2019, 29(1): 83-86. doi: 10.1038/s41422-018-0124-5
[6] ZHANG J, BU X, WANG H, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance[J]. Nature, 2018, 553(7686): 91-95. doi: 10.1038/nature25015
[7] LIM S O, LI C W, XIA W, et al. Deubiquitination and stabilization of PD-L1 by CSN5[J]. Cancer Cell, 2016, 30(6): 925-939. doi: 10.1016/j.ccell.2016.10.010
[8] DENG S, ZHOU X, XU J. Checkpoints under traffic control: from and to organelles[J]. Adv Exp Med Biol, 2020, 1248: 431-453. doi: 10.1007/978-981-15-3266-5_18
[9] FRAME S, COHEN P. GSK3 takes centre stage more than 20 years after its discovery[J]. Biochem J, 2001, 359(pt 1): 1-16. http://www.biochemj.org/content/359/1/1.full-text.pdf
[10] YANG Y, HSU J M, SUN L, et al. Palmitoylation stabilizes PD-L1 to promote breast tumor growth[J]. Cell Res, 2019, 29(1): 83-86. doi: 10.1038/s41422-018-0124-5
[11] ZHU Q, FU Y, LI L, et al. The functions and regulation of Otubains in protein homeostasis and diseases[J]. Ageing Res Rev, 2021, 67: 101303. doi: 10.1016/j.arr.2021.101303
[12] ZHU D, XU R, HUANG X, et al. Deubiquitinating enzyme OTUB1 promotes cancer cell immunosuppression via preventing ER-associated degradation of immune checkpoint protein PD-L1[J]. Cell Death Differ, 2021, 28(6): 1773-1789. doi: 10.1038/s41418-020-00700-z
[13] TOMCZAK K, CZERWI? SKA P, WIZNEROWICZ M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge[J]. Contemp Oncol: Pozn, 2015, 19(1a): A68-A77. http://www.scienceopen.com/document_file/ac4bb8d0-842c-4c65-924e-c0b532b5ab9c/PubMedCentral/ac4bb8d0-842c-4c65-924e-c0b532b5ab9c.pdf
[14] TANG Z, LI C, KANG B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45(w1): W98-W102. doi: 10.1093/nar/gkx247
[15] ZHOU Y, WU J, FU X, et al. OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer[J]. Mol Cancer, 2014, 13: 258. doi: 10.1186/1476-4598-13-258
[16] WENG W, ZHANG Q, XU M, et al. OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma[J]. Am J Transl Res, 2016, 8(5): 2234-2244. http://ajtr.org/files/ajtr0023747.pdf
[17] KARUNARATHNA U, KONGSEMA M, ZONA S, et al. OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance[J]. Oncogene, 2016, 35(11): 1433-1444. doi: 10.1038/onc.2015.208
[18] IGLESIAS-GATO D, CHUAN Y C, JIANG N, et al. Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo[J]. Mol Cancer, 2015, 14: 88. doi: 10.1186/s12943-015-0341-1
[19] WANG Y, WANG H, YAO H, et al. Regulation of PD-L1: emerging routes for targeting tumor immune evasion[J]. Front Pharmacol, 2018, 9: 536. doi: 10.3389/fphar.2018.00536
[20] ALTUN M, WALTER T S, KRAMER H B, et al. The human otubain2-ubiquitin structure provides insights into the cleavage specificity of poly-ubiquitin-linkages[J]. PLoS One, 2015, 10(1): e0115344. doi: 10.1371/journal.pone.0115344
[21] WIENER R, ZHANG X, WANG T, et al. The mechanism of OTUB1-mediated inhibition of ubiquitination[J]. Nature, 2012, 483(7391): 618-622. doi: 10.1038/nature10911
[22] FEDCHENKO N, REIFENRATH J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue-a review[J]. Diagn Pathol, 2014, 9: 221. doi: 10.1186/s13000-014-0221-9
[23] THOMPSON R H, KUNTZ S M, LEIBOVICH B C, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up[J]. Cancer Res, 2006, 66(7): 3381-3385. doi: 10.1158/0008-5472.CAN-05-4303
[24] HSU M C, HSIAO J R, CHANG K C, et al. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma[J]. Mod Pathol, 2010, 23(10): 1393-1403. doi: 10.1038/modpathol.2010.130
[25] HAMANISHI J, MANDAI M, IWASAKI M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer[J]. PNAS, 2007, 104(9): 3360-3365. doi: 10.1073/pnas.0611533104
[26] BAIETTI M F, SIMICEK M, ABBASI ASBAGH L, et al. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination[J]. EMBO Mol Med, 2016, 8(3): 288-303. doi: 10.15252/emmm.201505972
[27] LI Y, SUN X X, ELFERICH J, et al. Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1(Otub1) to suppress UbcH5 enzyme and stabilize p53 protein[J]. J Biol Chem, 2014, 289(8): 5097-5108. doi: 10.1074/jbc.M113.533109
-
期刊类型引用(2)
1. 孔令玉，朱天怡. 微小RNA-1180在非小细胞肺癌中的表达及其临床意义. 实用临床医药杂志. 2022(03): 76-80 . 
本站查看
2. 朱洪宇，史志敏. 微小RNA-338-3p调控信号转导和转录激活因子1对表皮生长因子受体酪氨酸激酶抑制剂耐药肺癌细胞株PC-9/GR中程序性死亡配体1表达和细胞凋亡的影响. 实用临床医药杂志. 2022(04): 100-105 . 本站查看
其他类型引用(0)
计量
- 文章访问数:
- HTML全文浏览量:
- PDF下载量:
- 被引次数: 2
苏公网安备 32100302010246号