«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

29卷

期数:

2023年02期

页码:

120-125，160

栏目:

基础医学

出版日期:

2023-03-20

文章信息/Info

Title:

Regulatory effect and molecular mechanism of LATS2 on malignant peripheral nerve sheath tumor cells

文章编号:

1006-8147（2023）02-0120-07

作者:

赵洋¹; 孙亚敏¹; 朱香熹²; 陈毓锴³; 朱泽¹

1.天津医科大学基础医学院病原生物学系，天津 300070;2.遵义医科大学珠海校区临床医学系，珠海519090;3.天津医科大学南开临床学院，天津300102

Author(s):

ZHAO Yang¹; SUN Ya-min¹; ZHU Xiang-xi²; CHEN Yu-kai³; ZHU Ze¹

1.Department of Pathogen Biology，School of Basic Medical Sciences，Tianjin Medical University，Tianjin 300070，China;2.Department of Clinical Medicine，Zhuhai Campus of Zunyi Medical University，Zhuhai 519090，China;3.Department of Nankai Clinical College， Tianjin Medical University，Tianjin 300102，China

关键词:

LATS2; 恶性周围神经鞘瘤; YAP/TAZ; 增殖; 迁移

Keywords:

LATS2; MPNST; YAP/TAZ; proliferation; migrate

分类号:

R739.43

DOI:

-

文献标志码:

A

摘要:

目的：探讨大肿瘤抑制激酶2（LATS2）对恶性周围神经鞘瘤（MPNST）细胞增殖和迁移的影响及机制。方法：LATS2过表达慢病毒感染ST88-14、STS26T细胞，实验分为阴性对照组及LATS2过表达组，利用CCK-8、细胞划痕实验检测过表达LATS2对细胞增殖、迁移的影响。实时荧光定量RT-PCR和免疫印迹实验检测细胞中LATS2、多梳抑制复合物2（PRC2）核心组分、Yes相关蛋白（YAP）、含有PDZ结合位点的转录共激活因子（TAZ）的mRNA和蛋白表达，以及组蛋白H3第27位赖氨酸上的三甲基化（H3K27me3）水平。结果：与对照组相比，LATS2过表达抑制ST88-14、STS26T细胞增殖（t=4.219、14.66、11.5，均P<0.05；t=5.674、7.118、10.77，均P<0.01）、迁移（t=4.838、4.736，均P<0.01）。与对照组相比，LATS2过表达不影响ST88-14、STS26T细胞中YAP/TAZ的mRNA和总蛋白水平，但升高其蛋白磷酸化水平（t=6.233、3.759，均P<0.01；t=3.44、2.947，均P<0.05）。与对照组相比，LATS2过表达不影响ST88-14、STS26T细胞中PRC2核心组分SUZ12、EZH2、EED的mRNA和蛋白水平，但H3K27me3水平明显升高（t=6.569、16.68，均P<0.01）。结论：LATS2在MPNST细胞系中表达下降，过表达LATS2升高H3K27me3表达水平，同时促进YAP/TAZ的磷酸化，从而抑制MPNST细胞的增殖、迁移，在MPNST中发挥肿瘤抑制因子的作用。

Abstract:

Objective：To investigate the effect and mechanism of large tumor suppressor kinase 2（LATS2）on the proliferation and migration of malignant peripheral never sheath tumor（MPNST）cells. Methods：LATS2 overexpressing lentivirus was infected with ST88-14 and STS26T cells，and the experiment was divided into negative control group and LATS2 overexpressing group，and the effect of LATS2 overexpression on cell proliferation and migration was detected using CCK-8 assay and cell scratch assay. Real-time fluorescence quantitative（RT-PCR）and Western blotting assays were performed to detect the mRNA and protein expression levels of LATS2，core fraction of polycomb repressive complex 2（PRC2），Yes-associated protein（YAP），transcriptional co-activator with PDZ-binding motif （TAZ），and the trimethylation level on lysine 27 of histone H3（H3K27me3）in the cells. Results：Compared with the control group，LATS2 overexpression inhibited the proliferation（t=4.219，14.66，11.5，all P<0.05；t=5.674，7.118，10.77，both P<0.01）and migration（t=4.838，4.736，both P<0.01）of ST88-14 and STS26T cells.Compared with the control group，LATS2 overexpression did not affect the mRNA and total protein levels of YAP and TAZ in ST88-14 and STS26T cells，but elevated their protein phosphorylation levels（t=6.233，3.759， both P<0.01；t=3.44，2.947，both P<0.05）. Compared with the control group，LATS2 overexpression did not affect the mRNA and protein levels of PRC2 core components SUZ12，EZH2 and EED in ST88-14 and STS26T cells，but H3K27me3 protein levels were significantly higher（t=6.569，16.68，both P<0.01）. Conclusion：LATS2 expression is decreased in MPNST cell lines，and overexpression of LATS2 increases the expression level of H3K27me3，while promoting the phosphorylation of YAP/TAZ，thus inhibiting the proliferation and migration of MPNST cells and acting as a tumor suppressor in MPNST.

参考文献/References:

[1] KI D H，HE S，RODIG S，et al. Overexpression of PDGFRA cooper－ates with loss ofNF1 and p53 to accelerate the molecular pathogene－sis of malign-antperipheral nerve sheath tumors[J]. Oncogene，2017， 36（8）：1058-1068.
[2] LEE W，TECKIE S，WIESNER T，et al. PRC2 is recurrently inacti－vated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors[J]. Nat Genet，2014，46（11）：1227-1232.
[3] 张静.MPNST中SUZ12过表达及敲除稳定细胞株的构建及意义[D].天津医科大学，2020.
[4] 周欣，李伟芸，王红艳. MST1/2调控先天免疫的功能和机制[J].遗传，2017，39（7）：642-649.
[5] ISFORT I，ELGES S，CYRA M，et al. Prevalence of the hippo effec－tors YAP1/TAZ in tumors of soft tissue and bone[J]. Sci Rep，2019， 9（1）：19704.
[6] ZANCONATO F，CORDENONSI M，PICCOLO S. YAP/TAZ at the roots of cancer[J]. Cancer Cell，2016，29（6）：783-803.
[7] WU LMN，DENG Y，WANG J，et al. Programming of Schwann cells by Lats-1/2-TAZ/YAP signaling drives malignant peripheral nerve sheath tumorigenesis[J]. Cancer Cell，2018，33（2）：292-308.
[8] TORIGATA K，DAISUKE O，MUKAI S，et al. LATS2 positively reg－ulates polycomb repressive complex 2[J]. PLoS One，2016，11（7）：e0158562.
[9] WIDEMANN B C. Current status of sporadic and neurofibromatosis type 1-as sociated malignant peripheral nerve sheath tumors[J]. Curr Oncol Rep，2009，11（4）：322-328.
[10] MIETTINEN M M，ANTONESCU C R，FLETCHER CDM，et al. Histopathologic eval-uation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis1-a consensus overview [J]. Hum Pathol，2017，67：1-10.
[11] CARROLL S L. The challenge of cancer genomics in rare nervous system neoplasms：malignant peripheral nerve sheath tumors as a paradigm for cross-species comparative oncogenomics[J]. Amer J Pat-hol，2016，186：464-477.
[12] LI Y，PEI J，XIA H，et al. Lats2，a putative tumor suppressor，inhibits G1/S transition[J]. Oncogene，2003，22（28）：4398-4405.
[13] ABE Y，OHSUGI M，HARAGUCHI K，et al. LATS2-Ajuba complex regulates gamma-tubulin recruitment to centrosomes and spindle or－ganization during mitosis[J]. FEBS Lett，2006，580（3）：782-788.
[14] REUVEN N，ADLER J，MELTSER V，et al. The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhi－bition of the tyrosine kinase c-Abl [J].Cell Death Differ，2013， 20（10）：1330-1340.
[15] GUO C，LIANG C，YANG J，et al. LATS2 inhibits cell proliferation and metas-tasis through the Hippo signaling pathway in glioma[J]. Oncol Rep，2019，41（5）：2753-2761.
[16] SHI Y，GENG D，ZHANG Y，et al. LATS2 inhibits malignant behav－iors of glioma cells via inactivating YAP[J]. J Mol Neurosci，2019， 68（1）：38-48.
[17] AYLON Y，MICHAEL D，SHMUELI A，et al. A positive feedback loop between the p53 and Lats2 tumor suppressors prevents te－traploidization[J]. Genes Dev，2006，20（19）：2687-2700.
[18] SHAO D，ZHAI P，HU C，et al. Lats2 promotes heart failure by stim－ulating p53-mediated apoptosis during pressure overload [J]. Sci Rep，2021，11（1）：23469.
[19] INOUE A，JANKE L J，GUDENAS B L，et al. A genetic mouse model with postn atal Nf1 and p53 loss recapitulates the histology and tran－scriptome of humanmalignant peripheral nerve sheath tumor [J]. Neurooncol Adv，2021，3（1）：v-dab129.
[20] WANG Q，LIU L，ZHANG S，et al. Long noncoding RNA NEAT1 suppresseshepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter re－gion and promotion of H3K2-7me3 methylation [J]. Exp Mol Med， 2020，52（3）：461-472.
[21] ZHANG P，GARNETT J，CREIGHTON C J，et al.EZH2-miR-30d-KPNB1 pathwayregulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis[J]. J Pathol，2014，232（3）：308-318.
[22] V魪LEZ-REYES G L，KOES N，RYU J H，et al. Transposon mutage－nesis-guided CRISPR/Cas9 screening strongly implicates dysregula－tion of Hippo/YAP signaling in malignant peripheral nerve sheath tumor development[J]. Cancers（Basel），2021，13（7）：1584.

相似文献/References:

[1]宋紫暄,李光明,张 静,等.H3K27三甲基化蛋白可作为MPNST的重要诊断标记物[J].天津医科大学学报,2018,24(04):353.
　SONG Zi-xuan,LI Guang-ming,ZHANG Jing,et al.H3K27me3 is a highly sensitive diagnostic marker for MPNST[J].Journal of Tianjin Medical University,2018,24(02):353.
[2]孙硕遥,高雅,朱香熹,等.吉非替尼通过促进H3K27甲基化水平抑制恶性周围神经鞘瘤细胞的增殖[J].天津医科大学学报,2021,27(03):211.
　SUN Shuo-yao,GAO Ya,ZHU Xiang-xi,et al.Gefitinib inhibits the proliferation of malignant peripheral nerve sheath tumor cells by promoting H3K27 methylation levels[J].Journal of Tianjin Medical University,2021,27(02):211.
[3]高雅,赵洋,朱香熹,等.司美替尼对恶性周围神经鞘瘤细胞增殖和凋亡的影响[J].天津医科大学学报,2022,28(01):40.
　GAO Ya,ZHAO Yang,ZHU Xiang-xi,et al.The effect of selumetinib on cell proliferation and apoptosis of malignant peripheral nerve sheath tumor[J].Journal of Tianjin Medical University,2022,28(02):40.
[4]孙亚敏,朱香熹,陈毓锴,等.萝卜硫素预防Ⅰ型神经纤维瘤病恶性进展的作用机制研究[J].天津医科大学学报,2024,30(02):105.[doi:10.20135/j.issn.1006-8147.2024.02.0105]
　SUN Yamin,ZHU Xiangxi,CHEN Yukai,et al.The effect and mechanism of sulforaphane in preventing malignant progression of neurofibromatosis type Ⅰ[J].Journal of Tianjin Medical University,2024,30(02):105.[doi:10.20135/j.issn.1006-8147.2024.02.0105]

备注/Memo

备注/Memo:

基金项目：国家自然科学基金（81672650）
作者简介：赵洋（1997-），女，硕士在读，研究方向：病原生物学；
通信作者：朱泽，E-mail：zhuze@tmu.edu.cn。

常用功能

更新日期/Last Update: 2023-04-30