NLK通过维持NF-&amp;#x003ba;B/P53平衡抑制前列腺炎-癌转化

王建; 丁聪聪; 陆岩; 李桐

doi:10.19401/j.cnki.1007-3639.2022.07.005

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NLK通过维持NF-κB/P53平衡抑制前列腺炎-癌转化

论著 | 更新时间：2025-12-31

- NLK通过维持NF-κB/P53平衡抑制前列腺炎-癌转化
- NLK inhibits the transformation from prostatitis to prostate cancer through maintaining NF-κB/P53 functional balance
- 中国癌症杂志 2022年32卷第7期页码：614-623
- 作者机构：
  
  广东医科大学广东省医学分子诊断重点实验室,广东东莞 523808
- 作者简介：
  
  王建（ORCID: 0000-0002-4903-4506）,博士,副研究员,E-mail: wangjian20031228@126.com。
- 基金信息：
  
  广东省自然科学基金(2018A030307039);广东医科大学重点培育项目(GDMUZ2019006)
- DOI：10.19401/j.cnki.1007-3639.2022.07.005
  中图分类号： R737.25
- 收稿：2021-11-29，
  
  纸质出版：2022-07-30
- 稿件说明：
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王建, 丁聪聪, 陆岩, 等. NLK通过维持NF-κB/P53平衡抑制前列腺炎-癌转化[J]. 中国癌症杂志, 2022,32(7):614-623.

Jian WANG, Congcong DING, Yan LU, et al. NLK inhibits the transformation from prostatitis to prostate cancer through maintaining NF-κB/P53 functional balance[J]. China Oncology, 2022, 32(7): 614-623.
王建, 丁聪聪, 陆岩, 等. NLK通过维持NF-κB/P53平衡抑制前列腺炎-癌转化[J]. 中国癌症杂志, 2022,32(7):614-623. DOI： 10.19401/j.cnki.1007-3639.2022.07.005.

Jian WANG, Congcong DING, Yan LU, et al. NLK inhibits the transformation from prostatitis to prostate cancer through maintaining NF-κB/P53 functional balance[J]. China Oncology, 2022, 32(7): 614-623. DOI： 10.19401/j.cnki.1007-3639.2022.07.005.

摘要

背景与目的：

前列腺炎症是促进其癌变的一个重要因素

但关键的分子机制不明。Nemo样激酶（Nemo-like kinase

NLK）在前列腺癌组织中的表达水平较良性组织显著降低

并且在前列腺癌细胞中沉默NLK表达可增强核因子-

#x003ba;B（nuclear factor-

#x003ba;B

NF-

#x003ba;B）的转录活性。本研究旨在探讨NLK调控前列腺炎-癌转化的作用及其机制

为应用抗炎新策略预防前列腺癌提供新的分子靶点和理论依据。

方法：

采用人前列腺上皮细胞RWPE-1与人急性单核细胞白血病细胞THP-1共培养的方法建立前列腺炎-癌转化细胞模型（RWPE-1/THP-1）。采用MTT实验及软琼脂集落形成实验检测

NLK

基因沉默或过表达对模型细胞增殖及恶性转化能力的影响。采用双荧光素酶报告基因实验检测

NLK

基因沉默或过表达对模型细胞NF-

#x003ba;B转录活性的影响。采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction

RTFQ-PCR）和蛋白质印迹法（Western blot）检测

NLK

基因沉默或过表达对模型细胞中核受体相关因子1（nuclear receptor-related fa

ctor 1

Nurr1）和鼠双微体基因2（murine double minute 2

MDM2）的mRNA表达和蛋白水平的影响。采用Western blot检测

NLK

基因沉默或过表达对模型细胞P53蛋白表达水平的影响。采用免疫荧光和免疫共沉淀技术分别检测Nurr1蛋白和P53蛋白在RWPE-1细胞中的定位分布及相互作用情况。

结果：

与RWPE-1/THP-1组相比

RWPE-1（NLK

#x02191;）/THP-1组的细胞增殖及转化能力显著降低

NF-

#x003ba;B转录活性显著减弱

Nurr1和MDM2的mRNA表达和蛋白水平显著下调

P53蛋白表达水平显著上升（

0.05）;与之相反

RWPE-1（NLK

#x02193;）/THP-1组的细胞增殖及转化能力显著升高

NF-

#x003ba;B转录活性显著增强

Nurr1和MDM2的mRNA表达和蛋白水平显著上调

P53蛋白表达水平显著下降（

0.05）。此外

Nurr1蛋白与P53蛋白在RWPE-1细胞的细胞核中存在共定位及相互作用。

结论：

NLK抑制前列腺炎-癌转化可能依赖于其对NF-

#x003ba;B/P53平衡的维护。

Abstract

Background and purpose:

Prostate inflammation is an important promoter of carcinogenesis. However

the key underlying mechanisms remain unknown. Nemo-like kinase (NLK) expression is significantly lower in prostate cancer tissues than in benign tissues; downregulation of NLK expression can enhance the transcriptional activity of nuclear factor-

#x003ba;B (NF-

#x003ba;B) in prostate cancer cells. This study aimed to explore the effects of NLK in regulating the transformation from prostatitis to prostate cancer and its mechanisms

to provide effective molecular targets and a new theoretical basis for novel anti-inflammatory strategies in prostate cancer prevention.

Methods:

The cell model of transformation from prostatitis to prostate cancer (RWPE-1/THP-1) was established by co-culture of human prostate epithelial cells RWPE-1 and human acute monocytic leukemia cells THP-1. The proliferation and transformation abilities of model cells with the silence or overexpression of NLK were investigated by MTT experiment and soft agar experiment

respectively. The effects of the silence or overexpression of NLK on NF-

#x003ba;B activity in model cells were investigated by luciferase assay. The mRNA expression and protein levels of nuclear receptor-related factor 1 (Nurr1) and murine double minute 2 (M

DM2) in model cells with the silence or overexpression of NLK were validated by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot

respectively. The effects of the silence or overexpression of NLK on P53 protein levels in model cells were investigated by Western blot. The co-localization of Nurr1 and P53 in RWPE-1 cells was investigated by immunofluorescence experiment. The interaction between Nurr1 and P53 in RWPE-1 cells was verified by co-immunoprecipitation assay.

Results:

Compared with the RWPE-1/THP-1 group

the proliferation and transformation abilities of model cells were decreased

the NF-

#x003ba;B activity was inhibited

the mRNA expression and protein levels of the Nurr1 and MDM2 were down-regulated

and the P53 protein levels were increased in RWPE-1 (NLK

#x02191;)/THP-1 group (

0.05). In contrast

the proliferation and transformation abilities of model cells were increased

the NF-

#x003ba;B activity was enhanced

the mRNA expression and protein levels of the Nurr1 and MDM2 were up-regulated

and the P53 protein levels were reduced in RWPE-1 (NLK

#x02193;)/THP-1 group (

0.05). Moreover

the Nurr1 and P53 were co-located in the nucleus of RWPE-1 cells and they interacted with each other.

Conclusion:

NLK can inhibit the transformation from prostatitis to prostate cancer

which may be related to maintaining NF-

#x003ba;B/P53 functional balance.

关键词

Keywords

references

中国抗癌协会泌尿男生殖系肿瘤专业委员会前列腺癌学组 . 前列腺癌筛查中国专家共识(2021年版) [J ] . 中国癌症杂志 , 2021 , 31 ( 5 ): 435 - 440 .

Prostate Cancer Group , Urogenital Tumor Professional Committee , Chinese Anti-Cancer Association . Chinese expert consensus on prostate cancer screening (2021 version) [J ] . China Oncol , 2021 , 31 ( 5 ): 435 - 440 .

李星 , 曾晓勇 . 中国前列腺癌流行病学研究进展 [J ] . 肿瘤防治研究 , 2021 , 48 ( 1 ): 98 - 102 .

LI X , ZENG X Y . Advances in epidemiology of prostate cancer in China [J ] . Cancer Res Prev Treat , 2021 , 48 ( 1 ): 98 - 102 .

CAI T , SANTI R , TAMANINI I , et al . Current knowledge of the potential links between inflammation and prostate cancer [J ] . Int J Mol Sci , 2019 , 20 ( 15 ): E3833.

ZHANG L , WANG Y , QIN Z Q , et al . Correlation between prostatitis, benign prostatic hyperplasia and prostate cancer: a systematic review and meta-analysis [J ] . J Cancer , 2020 , 11 ( 1 ): 177 - 189 . DOI: 10.7150/jca.37235 http://doi.org/10.7150/jca.37235 http://www.jcancer.org/v11p0177.htm http://www.jcancer.org/v11p0177.htm

PERLETTI G , MONTI E , MAGRI V , et al . The association between prostatitis and prostate cancer. Systematic review and meta-analysis [J ] . Arch Ital Urol Androl , 2017 , 89 ( 4 ): 259 - 265 . DOI: 10.4081/aiua.2017.4.259 http://doi.org/10.4081/aiua.2017.4.259 http://www.pagepressjournals.org/index.php/aiua/article/view/aiua.2017.4.259 http://www.pagepressjournals.org/index.php/aiua/article/view/aiua.2017.4.259

DOAT S , MAROUS M , REBILLARD X , et al . Prostatitis, other genitourinary infections and prostate cancer risk: influence of non-steroidal anti-inflammatory drugs? Results from the EPICAP study [J ] . Int J Cancer , 2018 , 143 ( 7 ): 1644 - 1651 . DOI: 10.1002/ijc.31565 http://doi.org/10.1002/ijc.31565 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31565 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31565

米志静 . Nemo样激酶与肿瘤相关性疾病研究进展 [J ] . 安徽医药 , 2016 , 20 ( 11 ): 2024 - 2027 .

MI Z J . Research progress of nemo-like kinase (NLK)and cancer-related diseases [J ] . Anhui Med Pharm J , 2016 , 20 ( 11 ): 2024 - 2027 .

HUANG Y , YANG Y , HE Y , et al . The emerging role of Nemo-like kinase (NLK) in the regulation of cancers [J ] . Tumour Biol , 2015 , 36 ( 12 ): 9147 - 9152 . DOI: 10.1007/s13277-015-4159-7 http://doi.org/10.1007/s13277-015-4159-7 http://link.springer.com/10.1007/s13277-015-4159-7 http://link.springer.com/10.1007/s13277-015-4159-7

WANG J , YANG Z H , CHEN H , et al . Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer [J ] . BMC Cancer , 2016 , 16 : 257 . DOI: 10.1186/s12885-016-2291-4 http://doi.org/10.1186/s12885-016-2291-4 http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2291-4 http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2291-4

STAAL J , BEYAERT R . Inflammation and NF-κB signaling in prostate cancer: mechanisms and clinical implications [J ] . Cells , 2018 , 7 ( 9 ): E122.

CHEN Y Z , XIN H H , PENG H , et al . Hypomethylation-linked activation of PLCE1 impedes autophagy and promotes tumorigenesis through MDM2-mediated ubiquitination and destabilization of p53 [J ] . Cancer Res , 2020 , 80 ( 11 ): 2175 - 2189 .

ZHU D L , ZHENG S , FANG C , et al . Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p [J ] . Cancer Lett , 2020 , 477 : 107 - 121 . DOI: 10.1016/j.canlet.2020.02.033 http://doi.org/10.1016/j.canlet.2020.02.033 https://linkinghub.elsevier.com/retrieve/pii/S0304383520301026 https://linkinghub.elsevier.com/retrieve/pii/S0304383520301026

ZHANG H H , LI S Z , ZHANG Z Y , et al . Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage [J ] . Cell Death Differ , 2014 , 21 ( 10 ): 1656 - 1663 . DOI: 10.1038/cdd.2014.78 http://doi.org/10.1038/cdd.2014.78 https://doi.org/10.1038/cdd.2014.78 https://doi.org/10.1038/cdd.2014.78

王建 , 陈华 , 丁聪聪 . 微管相关蛋白Nur77在前列腺癌转移中的作用及其机制的探讨 [J ] . 肿瘤 , 2018 , 38 ( 2 ): 111 - 119 .

WANG J , CHEN H , DING C C . The role of microtubule regulatory protein Nur77 in metastasis of prostate cancer and its mechanism [J ] . Tumor , 2018 , 38 ( 2 ): 111 - 119 .

FANG L Y , IZUMI K , LAI K P , et al . Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling [J ] . Cancer Res , 2013 , 73 ( 18 ): 5633 - 5646 .

LI S Z , ZHANG H H , LIANG J B , et al . Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKKβ [J ] . Biochim Biophys Acta , 2014 , 1843 ( 7 ): 1365 - 1372 .

SONG L , MARTINEZ L , ZIGMOND Z M , et al . c-Kit modifies the inflammatory status of smooth muscle cells [J ] . PeerJ , 2017 , 5 : e3418 . DOI: 10.7717/peerj.3418 http://doi.org/10.7717/peerj.3418 https://peerj.com/articles/3418 https://peerj.com/articles/3418

BEARD J A , TENGA A , HILLS J , et al . The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network [J ] . Sci Rep , 2016 , 6 : 25108 . DOI: 10.1038/srep25108 http://doi.org/10.1038/srep25108 https://doi.org/10.1038/srep25108 https://doi.org/10.1038/srep25108

CARRÀ G , LINGUA M F , MAFFEO B , et al . P53 vs NF- & #x003ba;B: the role of nuclear factor-kappa B in the regulation of p53 activity and vice versa [J ] . Cell Mol Life Sci , 2020 , 77 ( 22 ): 4449 - 4458 . DOI: 10.1007/s00018-020-03524-9 http://doi.org/10.1007/s00018-020-03524-9 https://doi.org/10.1007/s00018-020-03524-9 https://doi.org/10.1007/s00018-020-03524-9

LEE Y K , YI E Y , PARK S Y , et al . Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-κB signaling in HCT116 human colorectal carcinoma cells [J ] . BMB Rep , 2018 , 51 ( 6 ): 296 - 301 . DOI: 10.5483/BMBRep.2018.51.6.232 http://doi.org/10.5483/BMBRep.2018.51.6.232 http://www.bmbreports.org/journal/view.html?doi=10.5483/BMBRep.2018.51.6.232 http://www.bmbreports.org/journal/view.html?doi=10.5483/BMBRep.2018.51.6.232

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NLK通过维持NF-&#x003ba;B/P53平衡抑制前列腺炎-癌转化

NLK inhibits the transformation from prostatitis to prostate cancer through maintaining NF-&#x003ba;B/P53 functional balance

DOI：10.19401/j.cnki.1007-3639.2022.07.005

摘要

Abstract

关键词

Keywords

references

NLK通过维持NF-κB/P53平衡抑制前列腺炎-癌转化

NLK inhibits the transformation from prostatitis to prostate cancer through maintaining NF-κB/P53 functional balance