Silencing high mobility group protein B1 inhibits malignant biological behavior of glioblastoma cells

Zhuang LI; Wenjuan FU; Shuai WANG; Qin NIU; Xiaohong YAO

doi:10.16016/j.2097-0927.202109102

您当前的位置：

首页 >

文章列表页 >

Silencing high mobility group protein B1 inhibits malignant biological behavior of glioblastoma cells

Basic Medicine | 更新时间：2026-01-09

- Silencing high mobility group protein B1 inhibits malignant biological behavior of glioblastoma cells
- Journal of Army Medical University Vol. 44, Issue 5, Pages: 406-412(2022)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)第一附属医院病理学研究所
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81874087);the Project of Graduate Scientific Research Innovation of Chongqing(CYS21514)
- DOI：10.16016/j.2097-0927.202109102
  CLC： R341;R730.23;R730.264
- Received：13 September 2021，
  
  Revised：2021-10-16，
  
  Published：15 March 2022
- 稿件说明：
移动端阅览
Zhuang LI, Wenjuan FU, Shuai WANG, et al. Silencing high mobility group protein B1 inhibits malignant biological behavior of glioblastoma cells[J]. Journal of Army Medical University, 2022, 44(5): 406-412.
DOI：

Zhuang LI, Wenjuan FU, Shuai WANG, et al. Silencing high mobility group protein B1 inhibits malignant biological behavior of glioblastoma cells[J]. Journal of Army Medical University, 2022, 44(5): 406-412. DOI： 10.16016/j.2097-0927.202109102.

摘要

目的

探讨高迁移率族蛋白B1(high mobility group protein B1，HMGB1)在胶质母细胞瘤样本中的高表达对于胶质母细胞瘤侵袭能力及替莫唑胺治疗的影响。

方法

利用癌症和肿瘤基因图谱(the cancer genome atlas，TCGA)数据库中319例样本的HMGB1测序数据进行差异表达及生存分析。采用免疫组织化学(immunohistochemistry，IHC)检测HMGB1在本院生物样本库中收集的4例不同WHO分级胶质瘤样本中的表达。3例胶质瘤样本(分别为WHO Ⅱ、Ⅲ和Ⅳ级)和1例瘤旁脑组织(作为对照，其胶质瘤组织为WHO Ⅱ级)均来自于陆军军医大学第一附属医院生物样本库(2019年5-10月的男性住院患者，年龄40~88岁，中位年龄58.5岁；患者行胶质瘤组织切除术前未行放化疗，术后标本经病理组织学检查证实为胶质瘤)。采用慢病毒转染法构建沉默HMGB1的细胞株，Western blot检测HMGB1蛋白表达。CCK-8和Transwell检测HMGB1对细胞增殖和侵袭能力的影响。CCK-8检测沉默HMGB1对替莫唑胺的敏感性。替莫唑胺粉末溶于二甲基亚砜中制成100 mmol/L的储存液，使用时终浓度为250、500、1 000、1 500 μmol/L。

结果

TCGA数据库显示HMGB1 mRNA在肿瘤组织中表达显著上调(

0.01)，且随WHO级别的增加而增加，并与患者的预后显著负相关(

0.01)。沉默HMGB1的胶质母细胞瘤细胞株增殖能力降低(

0.05)，侵袭能力下降(

0.01)，且对替莫唑胺治疗更敏感(

0.05)。

结论

HMGB1在胶质母细胞瘤中显著上调，高表达的HMGB1促进了胶质母细胞瘤细胞的侵袭能力和替莫唑胺耐药。

Abstract

Objective

To investigate the effects of high expression of high mobility group protein B1 (HMGB1) on the invasion ability of glioblastoma (GBM) and the efficacy of temozolomide (TMZ) therapy.

Methods

The HMGB1 sequencing data of 319 GBM samples from TCGA database were gained for differential expression and survival analysis. Immunohistochemistry (IHC) was adopted to assess the expression of HMGB1 in 4 samples (3 glioma samples

with WHO grade Ⅱ

Ⅲ and Ⅳ

respectively

and 1 para-tumoral brain tissue as control) which were collected from our hospital's biobank (inpatients from May to October 2019

male

aged 40~88 years

median 58.5 years

being confirmed as glioma by histopathological examination after tissue resection

without radiotherapy or chemotherapy prior to surgery). Moreover

lentiviral vector was transfected to construct HMGB1 silenced GBM cell lines (U251 and LN229). Western blotting was performed to detect HMGB1 expression; CCK-8 and transwell assays were adopted to analyze the effect of HMGB1 on cell proliferation and invasion ability. Finally

the role of HMGB1 in TMZ therapy was evaluated by CCK-8 assay (TMZ powder was dissolved in dimethyl sulfoxide to prepare 100 mmol/L storage solution

and the final concentration used was 250

500

1 000 and 1 500 μmol/L

respectively).

Results

TCGA database showed that HMGB1 mRNA level was significantly upregulated in glioma tissue (

0.01)

increasing with WHO grade

and was negatively correlated with the prognosis of patients (

0.01). HMGB1 silenced GBM cells had decreased proliferation (

0.05) and inhibited invasion ability (

0.01)

and were more sensitive to TMZ therapy.

Conclusion

HMGB1 is remarkably up-regulated in GBM cells

and its high expression contributes to the enhanced invasion ability and temozolomide resistance of GBM cells.

关键词

Keywords

references

OMURO A, DEANGELIS L M. Glioblastoma and other malignant gliomas: a clinical review[J]. JAMA, 2013, 310(17): 1842-1850. DOI: 10.1001/jama.2013.280319.

FENG H B, WANG J, JIANG H R, et al . Β-elemene selectively inhibits the proliferation of glioma stem-like cells through the downregulation of Notch1[J ] . Stem Cells Transl Med, 2017, 6(3): 830-839. DOI: 10.5966/sctm.2016-0009.

GARNIER D, MEEHAN B, KISLINGER T, et al . Divergent evolution of temozolomide resistance in glioblastoma stem cells is reflected in extracellular vesicles and coupled with radiosensitization[J ] . Neuro Oncol, 2018, 20(2): 236-248. DOI: 10.1093/neuonc/nox142.

JOHANNESSEN T C A, BJERKVIG R, TYSNES B B. DNA repair and cancer stem-like cells: potential partners in glioma drug resistance?[J]. Cancer Treat Rev, 2008, 34(6): 558-567. DOI: 10.1016/j.ctrv.2008.03.125.

MURPHY S F, VARGHESE R T, LAMOUILLE S, et al . Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide[J ] . Cancer Res, 2016, 76(1): 139-149. DOI: 10.1158/0008-5472.can-15-1286.

TANG D, KANG R, LIVESEY K M, et al . Endogenous HMGB1 regulates autophagy[J ] . J Cell Biol, 2010, 190(5): 881-892. DOI: 10.1083/jcb.200911078.

WANG S, ZHANG Y. HMGB1 in inflammation and cancer[J]. J Hematol Oncol, 2020, 13(1): 116. DOI: 10.1186/s13045-020-00950-x.

LIU Y, YAN W, TOHME S, et al . Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9[J ] . J Hepatol, 2015, 63(1): 114-121. DOI: 10.1016/j.jhep.2015.02.009.

ANGELOPOULOU E, PIPERI C, ADAMOPOULOS C, et al . Pivotal role of high-mobility group box 1 (HMGB1) signaling pathways in glioma development and progression[J ] . J Mol Med, 2016, 94(8): 867-874. DOI: 10.1007/s00109-016-1435-y.

BASSI R, GIUSSANI P, ANELLI V, et al . HMGB1 as an a utocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration[J ] . J Neurooncol, 2008, 87(1): 23-33. DOI: 10.1007/s11060-007-9488-y.

VAN BEIJNUM J R, NOWAK-SLIWINSKA P, VAN DEN BOEZEM E, et al . Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1[J ] . Oncogene, 2013, 32(3): 363-374. DOI: 10.1038/onc.2012.49.

YAN W, CHANG Y, LIANG X, et al . High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases[J ] . Hepatology, 2012, 55(6): 1863-1875. DOI: 10.1002/hep.25572.

HOMBACH-KLONISCH S, MEHRPOUR M, SHOJAEI S, et al . Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response[J ] . Pharmacol Ther, 2018, 184: 13-41. DOI: 10.1016/j.pharmthera.2017.10.017.

[李德培, 陈忠平. 脑胶质瘤治疗现状与进展[J ] . 实用医学杂志, 2021, 37(18): 2312-2316. DOI: CNKI:SUN:SYYZ.0.2021-18-002 http://dx.doi.org/CNKI:SUN:SYYZ.0.2021-18-002 .

[CNKI: SUN: SYYZ. 0.2021-18-002. LI D P, CHEN Z P. Current statue and advances of treatment for gliomas[J ] . J Pract Med, 2021, 37(18): 2312-2316. DOI: CNKI:SUN:SYYZ.0.2021-18-002 http://dx.doi.org/CNKI:SUN:SYYZ.0.2021-18-002 .

董云朋, 程远, 陈晋. 沉默APN对胶质瘤细胞U251增殖、侵袭和凋亡的影响[J]. 第三军医大学学报, 2020, 42(9): 908-914. DOI: 10.16016/j.1000-5404.201912238.

DONG Y P, CHENG Y, CHEN J. Effects of silencing APN gene on proliferation, invasion and apoptosis of human glioma U251 cells[J]. J Third Mil Med Univ, 2020, 42(9): 908-914. DOI: 10.16016/j.1000-5404.201912238.

STUPP R, MASON W P, VAN DEN BENT M J, et al . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[J ] . N Engl J Med, 2005, 352(10): 987-996. DOI: 10.1056/nejmoa043330.

ARORA A, SOMASUNDARAM K. Glioblastoma vs temozolomide: can the red queen race be won?[J ] . Cancer Biol Ther, 2019, 20(8): 1083-1090. DOI: 10.1080/15384047.2019.1599662.

GAO Q, WANG S, CHEN X, et al . Cancer-cell-secreted CXCL11 promoted CD8 + T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC[J ] . J Immunother Cancer, 2019, 7(1): 42. DOI: 10.1186/s40425-019-0511-6..

GDYNIA G, KEITH M, KOPITZ J, et al . Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria[J ] . Cancer Res, 2010, 70(21): 8558-8568. DOI: 10.1158/0008-5472.can-10-0204.

KANG R, XIE Y, ZHANG Q, et al . Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer[J ] . Cell Res, 2017, 27(7): 916-932. DOI: 10.1038/cr.2017.51.

LOTZE M T, TRACEY K J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal[J]. Nat Rev Immunol, 2005, 5(4): 331-342. DOI: 10.1038/nri1594.

KUNIYASU H, OUE N, WAKIKAWA A, et al . Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer[J ] . J Pathol, 2002, 196(2): 163-170. DOI: 10.1002/path.1031.

SASAHIRA T, AKAMA Y, FUJⅡ K, et al . Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas[J ] . Virchows Arch, 2005, 446(4): 411-415. DOI: 10.1007/s00428-005-1210-x.

TAGUCHI A, BLOOD D C, DEL TORO G, et al . Blockade of RAGE-amphoterin sign alling suppresses tumour growth and metastases[J ] . Nature, 2000, 405(6784): 354-360. DOI: 10.1038/35012626.

GIAVARA S, KOSMIDOU E, HANDE M P, et al . Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability[J ] . Curr Biol, 2005, 15(1): 68-72. DOI: 10.1016/j.cub.2004.12.065.

CELONA B, WEINER A, DI FELICE F, et al . Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output[J ] . PLoS Biol, 2011, 9(6): e1001086. DOI: 10.1371/journal.pbio.1001086.

POLANSKÁ E, DOBŠÁKOVÁ Z, DVO ŘÁ ČKOVÁ M, et al . HMGB1 gene knockout in mouse embryonic fibroblasts results in reduced telomerase activity and telomere dysfunction[J ] . Chromosoma, 2012, 121(4): 419-431. DOI: 10.1007/s00412-012-0373-x.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Expression of LAPTM4B in glioma tissues and its effect on cell proliferation and invasion

Differential diagnostic efficacy of tumor vascular habitats based on DSC-PWI between glioblastoma and solitary metastatic brain tumors

Effects of LncRNA FGD5-AS1 on migration and invasion of gastric cancer cells by regulating miR-302b-3p/E2F1 axis

Expression of miR-616 in osteosarcoma and its role in proliferation, apoptosis, migration and invasion of tumor cells

Hypoxia characteristics and prognostic significance of glioblastoma MES-like subpopulation through multi-transcriptomics sequencing

Related Author

赵岗

张哲莹

杜宝顺

王阳

马欢

LI Xuan

WANG Hanwei

ZENG Linlan

Related Institution

Department of Radiology

Chongqing Clinical Research Centre of Imaging and Nuclear Medicine

Department of Pathology， Daping Hospital， Army Medical University

Department of Gastroenterology, Qingdao Central Hospital of Rehabilitation University

Endoscopy Center, Qingdao Central Hospital of Rehabilitation University

⁰