Generic placeholder image

当代肿瘤药物靶点

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

BRD4在胃癌中的过表达及其作为新型治疗靶点的临床意义

卷 24, 期 2, 2024

发表于: 12 July, 2023

页: [167 - 177] 页: 11

弟呕挨: 10.2174/1568009623666230606164030

价格: $65

摘要

背景:BRD4是溴域和额外末端结构域(BET)蛋白家族的成员,包含两个溴域和一个额外末端结构域,在几种人类恶性肿瘤中过表达。然而,其在胃癌中的表达尚未得到很好的阐明。 目的:本研究旨在阐明BRD4在胃癌中的过表达及其作为新的治疗靶点的临床意义。 方法:采集胃癌患者新鲜胃癌组织和石蜡包埋标本,分别采用Western Blot分析(WB)和免疫组化分析(IHC)检测BRD4的表达。分析BRD4表达与胃癌患者临床病理特征及生存的可能关系。采用MTT法、WB法、创面愈合法和Transwell侵袭法研究BRD4沉默对人胃癌细胞株的影响。 结果:结果显示,肿瘤组织和癌旁组织中表达量均显著高于正常组织(P < 0.01)。BRD4在胃癌组织中的表达水平与肿瘤分化程度(P = 0.033)、区域淋巴结转移(P = 0.038)、临床分期(P = 0.002)、生存情况(P = 0.000)密切相关,而与患者的性别(P = 0.564)、年龄(P = 0.926)、浸润深度(P = 0.619)无关。BRD4表达升高导致总生存率降低(P = 0.003)。在体外实验中,BRD4小干扰RNA导致BRD4蛋白表达显著降低,从而抑制胃癌细胞的增殖、迁移和侵袭。 结论:BRD4可能成为胃癌早期诊断、预后和治疗靶点的新型生物标志物。

关键词: 胃癌,BRD4,预后,siRNA, western blot,增殖。

图形摘要
[1]
Recio-Boiles, A.; Babiker, H.M. Gastric Cancer; StatPearls: Treasure Island, FL, 2022.
[2]
Chen, Z.; Zhang, P.; Xi, H.; Wei, B.; Chen, L.; Tang, Y. Recent advances in the diagnosis, staging, treatment, and prognosis of advanced gastric cancer: A literature review. Front. Med., 2021, 8, 744839.
[http://dx.doi.org/10.3389/fmed.2021.744839] [PMID: 34765619]
[3]
Cotterman, R.; Jin, V.X.; Krig, S.R.; Lemen, J.M.; Wey, A.; Farnham, P.J.; Knoepfler, P.S. N-Myc regulates a widespread euchromatic program in the human genome partially independent of its role as a classical transcription factor. Cancer Res., 2008, 68(23), 9654-9662.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1961] [PMID: 19047142]
[4]
Taniguchi, Y.; Kurokawa, Y.; Takahashi, T.; Mikami, J.; Miyazaki, Y.; Tanaka, K.; Makino, T.; Yamasaki, M.; Nakajima, K.; Mori, M.; Doki, Y. Prognostic value of trefoil factor 3 expression in patients with gastric cancer. World J. Surg., 2018, 42(12), 3997-4004.
[http://dx.doi.org/10.1007/s00268-018-4737-0] [PMID: 30039286]
[5]
Zheng, Q.; Wu, F.; Dai, W.Y.; Zheng, D.C.; Zheng, C.; Ye, H.; Zhou, B.; Chen, J.J.; Chen, P. Aberrant expression of UCA1 in gastric cancer and its clinical significance. Clin. Transl. Oncol., 2015, 17(8), 640-646.
[http://dx.doi.org/10.1007/s12094-015-1290-2] [PMID: 25903045]
[6]
Zhang, C.; Yuan, W.; Wu, Y.; Wan, X.; Gong, Y. Co-delivery of EGFR and BRD4 siRNA by cell-penetrating peptides-modified redox-responsive complex in triple negative breast cancer cells. Life Sci., 2021, 266, 118886.
[http://dx.doi.org/10.1016/j.lfs.2020.118886] [PMID: 33310044]
[7]
Wu, S.Y.; Lee, C.F.; Lai, H.T.; Yu, C.T.; Lee, J.E.; Zuo, H.; Tsai, S.Y.; Tsai, M.J.; Ge, K.; Wan, Y.; Chiang, C.M. Opposing functions of BRD4 isoforms in breast cancer. Mol. Cell, 2020, 78(6), 1114-1132.e10.
[http://dx.doi.org/10.1016/j.molcel.2020.04.034] [PMID: 32446320]
[8]
Fischer, D.; Bieber, T.; Li, Y.; Elsässer, H.P.; Kissel, T. A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: Effect of molecular weight on transfection efficiency and cytotoxicity. Pharm. Res., 1999, 16(8), 1273-1279.
[http://dx.doi.org/10.1023/A:1014861900478] [PMID: 10468031]
[9]
Ali, A.; Shafarin, J.; Unnikannan, H.; Al-Jabi, N.; Jabal, R.A.; Bajbouj, K.; Muhammad, J.S.; Hamad, M. Co-targeting BET bromodomain BRD4 and RAC1 suppresses growth, stemness and tumorigenesis by disrupting the c-MYC-G9a-FTH1axis and downregulation of HDAC1 in molecular subtypes of breast cancer. Int. J. Biol. Sci., 2021, 17(15), 4474-4492.
[http://dx.doi.org/10.7150/ijbs.62236] [PMID: 34803511]
[10]
Bauer, K.; Berghoff, A.S.; Preusser, M.; Heller, G.; Zielinski, C.C.; Valent, P.; Grunt, T.W. Degradation of BRD4 - a promising treatment approach not only for hematologic but also for solid cancer. Am. J. Cancer Res., 2021, 11(2), 530-545.
[PMID: 33575085]
[11]
Blee, A.M.; Liu, S.; Wang, L.; Huang, H. BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion. Oncotarget, 2016, 7(25), 38319-38332.
[http://dx.doi.org/10.18632/oncotarget.9513] [PMID: 27223260]
[12]
Fan, H.; Yuan, J.; Li, Y.; Jia, Y.; Li, J.; Wang, X.; Li, X. MKL1-induced lncRNA SNHG18 drives the growth and metastasis of non-small cell lung cancer via the miR-211-5p/BRD4 axis. Cell Death Dis., 2021, 12(1), 128.
[http://dx.doi.org/10.1038/s41419-021-03399-z] [PMID: 33500406]
[13]
Zhang, S.; Chen, Y.; Tian, C.; He, Y.; Tian, Z.; Wan, Y.; Liu, T. Dual-target inhibitors based on BRD4: Novel therapeutic approaches for cancer. Curr. Med. Chem., 2021, 28(9), 1775-1795.
[http://dx.doi.org/10.2174/0929867327666200610174453] [PMID: 32520674]
[14]
Shu, S.; Wu, H.J.; Ge, J.Y.; Zeid, R.; Harris, I.S.; Jovanović, B.; Murphy, K.; Wang, B.; Qiu, X.; Endress, J.E.; Reyes, J.; Lim, K.; Font-Tello, A.; Syamala, S.; Xiao, T.; Reddy, C.C.S.; Papachristou, E.K.; D’Santos, C.; Anand, J.; Hinohara, K.; Li, W.; McDonald, T.O.; Luoma, A.; Modiste, R.J.; Nguyen, Q.D.; Michel, B.; Cejas, P.; Kadoch, C.; Jaffe, J.D.; Wucherpfennig, K.W.; Qi, J.; Liu, X.S.; Long, H.; Brown, M.; Carroll, J.S.; Brugge, J.S.; Bradner, J.; Michor, F.; Polyak, K. Synthetic lethal and resistance interactions with BET bromodomain inhibitors in triple-negative breast cancer. Mol. Cell, 2020, 78(6), 1096-1113.e8.
[http://dx.doi.org/10.1016/j.molcel.2020.04.027] [PMID: 32416067]
[15]
Yin, M.; Guo, Y.; Hu, R.; Cai, W.L.; Li, Y.; Pei, S.; Sun, H.; Peng, C.; Li, J.; Ye, R.; Yang, Q.; Wang, N.; Tao, Y.; Chen, X.; Yan, Q. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nat. Commun., 2020, 11(1), 1833.
[http://dx.doi.org/10.1038/s41467-020-15290-0] [PMID: 32286255]
[16]
Ba, M.; Long, H.; Yan, Z.; Wang, S.; Wu, Y.; Tu, Y.; Gong, Y.; Cui, S. BRD4 promotes gastric cancer progression through the transcriptional and epigenetic regulation of c‐MYC. J. Cell. Biochem., 2018, 119(1), 973-982.
[http://dx.doi.org/10.1002/jcb.26264] [PMID: 28681984]
[17]
Qin, Z.; Wang, T.; Su, S.; Shen, L.; Zhu, G.; Liu, Q.; Zhang, L.; Liu, K.; Zhang, Y.; Zhou, Z.; Zhang, X.; Wen, L.; Yao, Y.; Sun, W.; Guo, Y.; Liu, K.; Liu, L.; Wang, X.; Wei, Y.; Wang, J.; Xiao, H.; Liu, P.; Bian, X.; Chen, D.; Wang, B. BRD4 promotes gastric cancer progression and metastasis through acetylation-dependent stabilization of snail. Cancer Res., 2019, 79(19), 4869-4881.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-0442] [PMID: 31311807]
[18]
Song, H.; Shi, L.; Xu, Y.; Xu, T.; Fan, R.; Cao, M.; Xu, W.; Song, J. BRD4 promotes the stemness of gastric cancer cells via attenuating miR-216a-3p-mediated inhibition of Wnt/β-catenin signaling. Eur. J. Pharmacol., 2019, 852, 189-197.
[http://dx.doi.org/10.1016/j.ejphar.2019.03.018] [PMID: 30876979]
[19]
Zhang, M.; Qiu, B.; Sun, M.; Wang, Y.; Wei, M.; Gong, Y.; Yan, M. Preparation of Black pepper (Piper nigrum L.) essential oil nanoparticles and its antitumor activity on triple negative breast cancer in vitro. J. Food Biochem., 2022, 46(12), e14406.
[http://dx.doi.org/10.1111/jfbc.14406] [PMID: 36121189]
[20]
Walter, L.O.; Maioral, M.F.; Silva, L.O.; Speer, D.B.; Campbell, S.C.; Gallimore, W.; Falkenberg, M.B.; Santos-Silva, M.C. Involvement of the NF‐κB and PI3K/Akt/MTOR pathways in cell death triggered by stypoldione, an o‐quinone isolated from the brown algae Stypopodium zonale. Environ. Toxicol., 2022, 37(6), 1297-1309.
[http://dx.doi.org/10.1002/tox.23484] [PMID: 35128807]
[21]
Sekiguchi, M.; Oda, I.; Matsuda, T.; Saito, Y. Epidemiological trends and future perspectives of gastric cancer in eastern Asia. Digestion, 2022, 103(1), 22-28.
[http://dx.doi.org/10.1159/000518483] [PMID: 34515086]
[22]
Sexton, R.E.; Al Hallak, M.N.; Diab, M.; Azmi, A.S. Gastric cancer: A comprehensive review of current and future treatment strategies. Cancer Metastasis Rev., 2020, 39(4), 1179-1203.
[http://dx.doi.org/10.1007/s10555-020-09925-3] [PMID: 32894370]
[23]
Vogelaar, I.P.; van der Post, R.S.; Bisseling, T.M.; van Krieken, J.H.J.M.; Ligtenberg, M.J.L.; Hoogerbrugge, N. Familial gastric cancer: Detection of a hereditary cause helps to understand its etiology. Hered. Cancer Clin. Pract., 2012, 10(1), 18.
[http://dx.doi.org/10.1186/1897-4287-10-18] [PMID: 23231819]
[24]
Tan, P.; Yeoh, K.G. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology, 2015, 149(5), 1153-1162.e3.
[http://dx.doi.org/10.1053/j.gastro.2015.05.059] [PMID: 26073375]
[25]
Bierne, H.; Hamon, M.; Cossart, P. Epigenetics and bacterial infections. Cold Spring Harb. Perspect. Med., 2012, 2(12), a010272.
[http://dx.doi.org/10.1101/cshperspect.a010272] [PMID: 23209181]
[26]
Feng, W.; Ding, Y.; Zong, W.; Ju, S. Non-coding RNAs in regulating gastric cancer metastasis. Clin. Chim. Acta, 2019, 496, 125-133.
[http://dx.doi.org/10.1016/j.cca.2019.07.003] [PMID: 31276633]
[27]
Grady, W.M.; Yu, M.; Markowitz, S.D. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Gastroenterology, 2021, 160(3), 690-709.
[http://dx.doi.org/10.1053/j.gastro.2020.09.058] [PMID: 33279516]
[28]
Fujisawa, T.; Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol., 2017, 18(4), 246-262.
[http://dx.doi.org/10.1038/nrm.2016.143] [PMID: 28053347]
[29]
Filippakopoulos, P.; Knapp, S. Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov., 2014, 13(5), 337-356.
[http://dx.doi.org/10.1038/nrd4286] [PMID: 24751816]
[30]
Wang, N; Wu, RL; Tang, DL; Kang, R The BET family in immunity and disease. Signal Transduct Tar., 2021, 6(1), 23.
[http://dx.doi.org/10.1038/s41392-020-00384-4]
[31]
Hu, Y.; Zhou, J.; Ye, F.; Xiong, H.; Peng, L.; Zheng, Z.; Xu, F.; Cui, M.; Wei, C.; Wang, X.; Wang, Z.; Zhu, H.; Lee, P.; Zhou, M.; Jiang, B.; Zhang, D. BRD4 inhibitor inhibits colorectal cancer growth and metastasis. Int. J. Mol. Sci., 2015, 16(1), 1928-1948.
[http://dx.doi.org/10.3390/ijms16011928] [PMID: 25603177]
[32]
Jiao, F.; Han, T.; Yuan, C.; Liang, Y.; Cui, J.; Zhuo, M.; Wang, L. Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer. Cancer Cell Int., 2020, 20(1), 55.
[http://dx.doi.org/10.1186/s12935-020-1135-0] [PMID: 32099528]
[33]
Tan, Y.F.; Wang, M.; Chen, Z.Y.; Wang, L.; Liu, X.H. Inhibition of BRD4 prevents proliferation and epithelial–mesenchymal transition in renal cell carcinoma via NLRP3 inflammasome-induced pyroptosis. Cell Death Dis., 2020, 11(4), 239.
[http://dx.doi.org/10.1038/s41419-020-2431-2] [PMID: 32303673]
[34]
Niu, X.; Wang, W.; Liang, T.; Li, S.; Yang, C.; Xu, X.; Li, L.; Liu, S. CPI‐203 improves the efficacy of anti‐PD‐1 therapy by inhibiting the induced PD‐L1 overexpression in liver cancer. Cancer Sci., 2022, 113(1), 28-40.
[http://dx.doi.org/10.1111/cas.15190] [PMID: 34727389]
[35]
Yigitliler, A.; Renner, J.; Simon, C.; Schneider, M.; Stubenrauch, F.; Iftner, T. BRD4S interacts with viral E2 protein to limit human papillomavirus late transcription. J. Virol., 2021, 95(11), e02032-20.
[http://dx.doi.org/10.1128/JVI.02032-20] [PMID: 33731454]
[36]
Wang, X.; Helfer, C.M.; Pancholi, N.; Bradner, J.E.; You, J. Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J. Virol., 2013, 87(7), 3871-3884.
[http://dx.doi.org/10.1128/JVI.03068-12] [PMID: 23365439]
[37]
Sun, H.Y.; Du, S.T.; Li, Y.Y.; Deng, G.T.; Zeng, F.R. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J. Gastrointest. Oncol., 2022, 14(1), 75-89.
[http://dx.doi.org/10.4251/wjgo.v14.i1.75] [PMID: 35116104]
[38]
Saffar, H.; Okhovat, H.; Arbabsoleymani, S.; Tavangar, S.M.; Khoshnevisan, A.; Hajinasrollah, G.; Hamidi Afra, Z.; Saffar, H. The utility of phosphohistone H3 in inter-observer variability of mitotic count in meningioma, is there any benefit? Asian Pac. J. Cancer Prev., 2021, 22(7), 2049-2052.
[http://dx.doi.org/10.31557/APJCP.2021.22.7.2049] [PMID: 34319026]
[39]
Tu, Y.; Jiang, P.; Zhang, J.; Jiang, S.; Yi, Q.; Yuan, R. The positive threshold of the immunohistochemical parameter Ki67 for predicting the recurrence of cervical cancer. Int. J. Gynaecol. Obstet., 2022, 158(2), 330-337.
[http://dx.doi.org/10.1002/ijgo.14005] [PMID: 34735721]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy