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中华脑科疾病与康复杂志(电子版) ›› 2021, Vol. 11 ›› Issue (03) : 132 -138. doi: 10.3877/cma.j.issn.2095-123X.2021.03.002

基础研究

Tenascin-C在胶质瘤中的表达及对替莫唑胺疗效的影响
陈璐1, 李启露1, 李姝君2,()   
  1. 1. 529300 广东开平,广东医科大学附属开平医院肿瘤科
    2. 524400 广东湛江,广东医科大学附属医院肿瘤科
  • 收稿日期:2021-03-19 出版日期:2021-06-15
  • 通信作者: 李姝君

Expression of Tenascin-C in glioma and its effect on temozolomide therapeutic value

Lu Chen1, Qilu Li1, Shujun Li2,()   

  1. 1. Department of Oncology, Kaiping Hospital Affiliated to Guangdong Medical University, Kaiping 529300, China
    2. Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524400, China
  • Received:2021-03-19 Published:2021-06-15
  • Corresponding author: Shujun Li
引用本文:

陈璐, 李启露, 李姝君. Tenascin-C在胶质瘤中的表达及对替莫唑胺疗效的影响[J]. 中华脑科疾病与康复杂志(电子版), 2021, 11(03): 132-138.

Lu Chen, Qilu Li, Shujun Li. Expression of Tenascin-C in glioma and its effect on temozolomide therapeutic value[J]. Chinese Journal of Brain Diseases and Rehabilitation(Electronic Edition), 2021, 11(03): 132-138.

目的

研究Tenascin-C(TNC)在胶质瘤中的表达特征和临床意义,以及TNC对替莫唑胺(TMZ)治疗胶质瘤疗效的影响。

方法

通过人类蛋白组数据库和中国胶质瘤患者基因组图谱(CGGA)数据库挖掘TNC在胶质瘤中的表达水平特征及临床意义;通过TNC shRNA质粒和过表达TNC质粒及慢病毒抑制或增强U87MG和U251细胞中TNC的蛋白表达水平,利用CCK-8检测细胞增殖和存活,以及肿瘤细胞U87MG在裸鼠颅内原位成瘤等实验评价TNC对TMZ治疗胶质瘤疗效的影响。

结果

(1)人类蛋白组数据库显示,TNC在正常神经细胞中不表达或低表达,在脑胶质瘤细胞(U138MG、U87MG、U251)中高转录。(2)CGGA数据库显示,TNC基因在WHO Ⅳ级胶质母细胞瘤中的转录水平高于WHO Ⅱ、Ⅲ级胶质瘤(P<0.05)。异柠檬酸脱氢酶(IDH)野生型组TNC mRNA水平显著高于IDH突变型组,无1p/19q联合缺失组显著高于1p/19q联合缺失组(均P<0.05)。高TNC mRNA水平患者的中位生存期(17.33个月)显著短于低TNC mRNA水平患者(89.87个月)(P<0.05)。(3)TNC过表达后显著减弱了TMZ对U87MG和U251细胞增殖的抑制作用和肿瘤杀伤作用(P<0.05),而干扰TNC表达后显著增强了TMZ对U87MG和U251细胞增殖的抑制作用和肿瘤杀伤作用(P<0.05)。干扰TNC表达后显著增强了TMZ对裸鼠颅内U87MG的抑制作用(P<0.05),而过表达TNC后显著减弱了TMZ对裸鼠颅内U87MG的抑制作用(P<0.05)。

结论

TNC在胶质瘤中高表达,并且与患者的生存预后负相关。TNC水平显著调控TMZ治疗胶质瘤的效果,抑制TNC的表达可能是改善TMZ疗效的有效手段。

Objective

To investigate the expression characteristics and clinical relevance of Tenascin-C (TNC) in glioma and the effect of TNC on the efficacy of temozolomide (TMZ) in the treatment of glioma.

Methods

The Human Protein Atlas and Chinese Glioma Genome Atlas (CGGA) database were used to evaluate the expression level of TNC in glioma and its clinical significance. TNC shRNA plasmid and overexpression plasmid of TNC, and the related lentivirus were used to inhibit or enhance the expression of TNC protein in U87MG and U251 cells. Cell proliferation and survival were detected by CCK-8 assay, and tumor cells U87MG in situ tumor formation in nude mice, were used to evaluate the effect of TNC on the efficacy of TMZ in the treatment of glioma.

Results

(1)The Human Protein Atlas database showed that TNC was not expressed or low expressed in normal nerve cells, and was highly expressed in glioma cells (U138MG, U87MG, U251). (2)In the CGGA database, the transcription level of TNC in WHO grade Ⅳ glioblastoma was significantly higher than that in WHO grade Ⅱ and WHO grade Ⅲ glioblastoma (P<0.05). The mRNA level of TNC in IDH wild-type glioma was significantly higher than that in IDH mutant glioma (P<0.05), as well as significantly higher in patients without 1P/19q combined deletion glioma than 1P/19q combined deletion glioma (P<0.05). Patients with high TNC mRNA levels had significantly shorter survival outcomes (17.33 months) compared with those with low TNC mRNA levels (89.87 months) (P<0.05). (3)TNC overexpression significantly reduced the proliferation inhibition and tumor killing effect of TMZ on U87MG and U251 cells (P<0.05), and interference with TNC expression significantly enhanced the proliferation inhibition and tumor killing effect of TMZ on U87MG and U251 cells (P<0.05). Interfering TNC expression significantly enhanced the inhibitory effect of TMZ on intracranial U87MG in nude mice (P<0.05), and the overexpression of TNC significantly reduced the inhibitory effect of TMZ on intracranial U87MG in nude mice (P<0.05).

Conclusion

TNC is highly expressed in glioma and is negatively correlated with survival prognosis of patients. TNC level significantly regulates the efficacy of TMZ in the treatment of glioma, and inhibition of TNC expression may be an effective means to improve the efficacy of TMZ.

图1 TNC基因在胶质瘤中的转录水平特征
图2 TNC与胶质瘤患者的临床预后关系
图3 TNC对TMZ治疗胶质瘤的影响
[1]
Meyer MA. Malignant gliomas in adults[J]. N Engl J Med, 2008, 359(17): 1850; author reply 1850.
[2]
von Neubeck C, Seidlitz A, Kitzler HH, et al. Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs[J]. Br J Radiol, 2015, 88(1053): 20150354.
[3]
Le Rhun E, Preusser M, Roth P, et al. Molecular targeted therapy of glioblastoma[J]. Cancer Treat Rev, 2019, 80: 101896.
[4]
Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy[J]. N Engl J Med, 2016, 375(26): 2561-2569.
[5]
Berghoff AS, Preusser M. Does neoadjuvant anti-PD1 therapy improve glioblastoma outcome?[J]. Nat Rev Neurol, 2019, 15(6): 314-315.
[6]
Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma[J]. J Clin Oncol, 2009, 27(23): 3861-3867.
[7]
Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial[J]. J Clin Oncol, 2013, 31(32): 4085-4091.
[8]
Dhaouadi S, Ben Abderrazek R, Loustau T, et al. Novel human tenascin-C function-blocking camel single domain nanobodies[J]. Front Immunol, 2021, 12: 635166.
[9]
Wiemann S, Reinhard J, Faissner A. Immunomodulatory role of the extracellular matrix protein tenascin-C in neuroinflammation[J]. Biochem Soc Trans, 2019, 47(6): 1651-1660.
[10]
Midwood KS, Chiquet M, Tucker RP, et al. Tenascin-C at a glance[J]. J Cell Sci, 2016, 129(23): 4321-4327.
[11]
Angel I, Pilo Kerman O, Rousso-Noori L, et al. Tenascin C promotes cancer cell plasticity in mesenchymal glioblastoma[J]. Oncogene, 2020, 39(46): 6990-7004.
[12]
Hotchkiss KM, Sampson JH. Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor[J]. J Neurooncol, 2021, 151(1): 55-62.
[13]
Lee SY. Temozolomide resistance in glioblastoma multiforme[J]. Genes Dis, 2016, 3(3): 198-210.
[14]
Bijelic D, Adzic M, Peric M, et al. Different functions of recombinantly expressed domains of tenascin-C in glial scar formation[J]. Front Immunol, 2020, 11: 624612.
[15]
Maqbool A, Spary EJ, Manfield IW, et al. Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4[J]. World J Cardiol, 2016, 8(5): 340-350.
[16]
Sonoda Y. Clinical impact of revisions to the WHO classification of diffuse gliomas and associated future problems[J]. Int J Clin Oncol, 2020, 25(6): 1004-1009.
[17]
Tang YA, Chen CH, Sun HS, et al. Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer[J]. Neclei Acids Res, 2015, 43(3): 1593-1608.
[18]
Wang T, Srivastava S, Hartman M, et al. High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer[J]. Oncotarget, 2016, 7(34): 55155-55168.
[19]
Nie S, Gurrea M, Zhu J, et al. Tenascn-C: a novel candidate marker for cancer stem cells in glioblatoma identified by tissue microarray[J]. J Proteome Res, 2015, 14(2): 814-822.
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