山东大学学报(医学版) ›› 2017, Vol. 55 ›› Issue (4): 65-70.doi: 10.6040/j.issn.1671-7554.0.2016.1467
张智慧,王丽丽,高华,张健,李娟,李远,武春晓,卢志明
ZHANG Zhihui, WANG Lili, GAO Hua, ZHANG Jian, LI Juan, LI Yuan, WU Chunxiao, LU Zhiming
摘要: 目的 研究缺氧诱导因子-1α(HIF-1α)和程序性死亡因子配体1(PD-L1)在肺腺癌中的表达与临床病理特征的关系,探讨肺腺癌中HIF-1α对PD-L1的调控作用。 方法 应用免疫组织化学方法检测99例肺腺癌组织中HIF-1α、PD-L1的表达。CoCl2模拟化学性缺氧处理肺腺癌细胞,并将其分为正常组及CoCl2组,qRT-PCR检测HIF-1α、PD-L1 mRNA表达,Western blotting检测HIF-1α、PD-L1蛋白表达。siRNA-HIF-1α瞬时转染肺腺癌细胞,并将其分为阴性对照组及siR-HIF-1α组,qRT-PCR、Western blotting检测转染效率及PD-L1 mRNA和蛋白的表达。 结果 99例肺腺癌组织中,HIF-1α和PD-L1的阳性率分别为47.48%和34.34%,HIF-1α表达水平与患者年龄和临床分期有关(P<0.05),PD-L1表达水平与患者临床分期有关(P<0.05),HIF-1α蛋白表达与PD-L1蛋白表达呈正相关(P<0.01)。与正常组相比,CoCl2组细胞中HIF-1α蛋白表达水平明显升高(t=-2.394, P=0.029),PD-L1 mRNA及蛋白表达水平随之明显升高(t=-3.146, P=0.006; t=-3.308, P=0.004)。与阴性对照组相比,siR-HIF-1α组沉默处理细胞后,PD-L1 mRNA及蛋白表达水平显著降低(t=2.746, P=0.014; t=2.339, P=0.033)。 结论 肺腺癌组织中HIF-1α和PD-L1明显共表达;PD-L1表达受HIF-1α调控。
中图分类号:
| [1] Zheng YW, Li RM, Zhang XW, et al. Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome[J]. Cancer Invest, 2013, 31(3): 197-205. [2] Lortet-Tieulent J, Soerjomataram I, Ferlay J, et al. International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women[J]. Lung Cancer, 2014, 84(1): 13-22. [3] Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion[J]. Nat Med, 2002, 8(8): 793-800. [4] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17): 1627-1639. [5] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(2): 123-135. [6] Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(21): 2018-2028. [7] Shien K, Papadimitrakopoulou VA, Wistuba II. Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer[J]. Lung Cancer, 2016, 99(2016): 79-87. [8] Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review[J]. JAMA Oncol, 2016, 2(9): 1217-1222. [9] Bally AP, Austin JW, Boss JM. Genetic and epigenetic regulation of PD-1 expression[J]. J Immunol, 2016, 196(6): 2431-2437. [10] Semenza GL. Oxygen sensing, homeostasis, and disease[J]. N Engl J Med, 2011, 365(6): 537-547. [11] Barsoum IB, Smallwood CA, Siemens DR, et al. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells[J]. Cancer Res, 2014, 74(3): 665-674. [12] Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation[J]. J Exp Med, 2014, 211(5): 781-790. [13] Chang YL, Yang CY, Lin MW, et al. High co-expression of PD-L1 and HIF-1α correlates with tumor necrosis in pulmonary pleomorphic carcinoma[J]. Eur J Cancer, 2016, 60:125-135. [14] Chen TC, Wu CT, Wang CP, et al. Associations among pretreatment tumor necrosis and the expression of HIF-1α and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof[J]. Oral Oncol, 2015, 51(11): 1004-1010. [15] Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer staging project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming(seventh)edition of the TNM classification of malignant tumors[J]. J Thorac Oncol, 2007, 2(8): 694-705. [16] Kishimoto K, Yoshida S, Ibaragi S, et al. Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer[J]. Oral Oncol, 2012, 48(11): 1120-1127. [17] Urano N, Fujiwara Y, Doki Y, et al. Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma[J]. Gastric Cancer, 2006, 9(1): 44-49. [18] Miyake K, Yoshizumi T, Imura S, et al. Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation[J]. Pancreas, 2008, 36(3): 1-9. [19] Kimbro KS, Simons JW. Hypoxia-inducible factor-1 in human breast and prostate cancer[J]. Endocr Relat Cancer, 2006, 13(3): 739-749. [20] Liu SY, Chang LC, Pan LF, et al. Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma[J]. Oral Oncol, 2008, 44(3): 277-285. [21] Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy[J]. Acta Pharm Sin B, 2015, 5(5): 378-389. [22] Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis[J]. Cell Death Differ, 2008, 15(4): 678-685. [23] Rankin EB, Giaccia AJ. Hypoxic control of metastasis[J]. Science, 2016, 352(6282): 175-180. [24] Palazon A, Goldrath AW, Nizet V, et al. HIF transcription factors, inflammation, and immunity[J]. Immunity, 2014, 41(4): 518-528. [25] 刘金峰, 张楠, 徐超, 等. HIF-1α与HGF在非小细胞肺癌中的共表达及其与淋巴管生成的关系[J]. 山东大学学报(医学版), 2011, 49(11): 112-116. LIU Jinfeng, ZHANG Nan, XU Chao, et al. Co-expression of hypoxia-inducible factor-1α and hepatocyte growth factor in non-small-cell lung cancer and their association with lymphangiogenesis[J]. Journal of Shandong University(Health Sciences), 2011, 49(11): 112-116. [26] 张浩, 任秀红, 刘莉. PD-L1和EGFR在非小细胞肺癌组织中的表达及相关性分析[J]. 疑难病杂志, 2015, 14(8): 786-792. ZHANG Hao, REN Xiuhong, LIU Li. Expression of PD-L1 and EGFR in non-small cell lung cancer and its clinical relationships[J]. Chin J Diffic and Compl Cas, 2015, 14(8): 786-792. [27] Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma[J]. Int J Cancer, 2016, 139(2): 396-403. [28] Koh J, Jang JY, Keam B, et al. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor(HIF)-1α and STAT3[J]. Oncoimmunology, 2015, 5(3): e1108514. |
| [1] | 殷悦,莫振飞,吴培昕,刘金霞,魏元辉,任佳博,李春笋. GPX1基因在肺癌中的表达特征及其对肺腺癌细胞增殖、迁移、侵袭、凋亡的影响[J]. 山东大学学报 (医学版), 2026, 64(1): 65-73. |
| [2] | 韩觉明,王晖,吴倩,郑慧玲,朱琳. B4GALNT4促进肺腺癌细胞增殖、迁移和侵袭能力[J]. 山东大学学报 (医学版), 2025, 63(7): 23-31. |
| [3] | 蔡佳莹,王靖婷,王增萍,王璟,郏雁飞,马晓丽. α5-nAChR对慢性应激肺腺癌荷瘤小鼠疑核c-Fos表达的影响[J]. 山东大学学报 (医学版), 2025, 63(4): 69-74. |
| [4] | 王靖婷,王璟,鲁艺,李静坦,李强,郏雁飞,马晓丽. α5-nAChR与MHC-I在肺腺癌中的表达及相关性[J]. 山东大学学报 (医学版), 2024, 62(5): 72-78. |
| [5] | 杨闯,张荣雨,宋彬,王程君,赵文,玄甜甜,李际盛. 阿美替尼一线治疗EGFR突变肺腺癌伴大疱性类天疱疮1例并文献复习[J]. 山东大学学报 (医学版), 2024, 62(12): 32-37. |
| [6] | 孟健丽,王庆港. 生物信息学方法探讨VPS72在肺腺/鳞癌中的表达及潜在作用机制[J]. 山东大学学报 (医学版), 2023, 61(8): 40-49. |
| [7] | 杜圣红,李晓梅,陈晨,王玲. 鼻型弥漫大B细胞淋巴瘤合并肺腺癌1例并文献复习[J]. 山东大学学报 (医学版), 2023, 61(8): 111-115. |
| [8] | 刘士标,张淑君,李培龙,杜鲁涛,王传新. cg20657709位点甲基化对肺腺癌早期诊断的初步探讨[J]. 山东大学学报 (医学版), 2023, 61(4): 18-25. |
| [9] | 赵启迪,王凯,赵小刚,闫涛,王亚东,杜贾军. 基于SEER数据库构建并验证IIIB期非小细胞肺癌患者预后模型[J]. 山东大学学报 (医学版), 2023, 61(10): 23-37. |
| [10] | 洪慧,张卫海,李惠娴,李伟伟,张金岭. 异时性阑尾印戒细胞癌合并肺腺癌双原发癌1例[J]. 山东大学学报 (医学版), 2022, 60(8): 130-132. |
| [11] | 徐歌,李青,张灿灿,田永杰. 子宫腺肌病组织及原代细胞中PARP-1、HIF-1α的表达及临床意义[J]. 山东大学学报 (医学版), 2022, 60(4): 55-61. |
| [12] | 郑昊天,王光辉,赵小刚,王亚东,曾榆凯,杜贾军. 基于数据库LKB1突变肺腺癌DNA异常甲基化位点构建的预后风险模型[J]. 山东大学学报 (医学版), 2022, 60(3): 51-58. |
| [13] | 柴小雪,叶辉,吕欣然,丁续超,甄秋来,杜娟,曹莉莉. POU4F3表达对118例肺腺癌患者预后评估及对肺腺癌细胞株迁移的影响[J]. 山东大学学报 (医学版), 2021, 59(11): 8-18. |
| [14] | 庞兆飞,柳勇,赵小刚,闫涛,陈效伟,杜贾军. 基于公共数据库构建肺腺癌肿瘤干性评分模型预测免疫治疗疗效[J]. 山东大学学报 (医学版), 2021, 59(11): 19-28. |
| [15] | 杨秀婷,刘启功,左萍,刘正湘,左后娟. CD151-MUT突变对肺腺癌细胞A549迁移的影响及机制[J]. 山东大学学报 (医学版), 2020, 58(3): 81-86. |
|
||