Mechanistic study on PLK4 regulation of invasion, proliferation and apoptosis in oral squamous cell carcinoma

Huan QIN; Jie WANG; Jie YANG; Yingjie HUA; Huijuan QU; Honghai JI

doi:10.19401/j.cnki.1007-3639.2025.04.004

您当前的位置：

首页 >

文章列表页 >

Mechanistic study on PLK4 regulation of invasion, proliferation and apoptosis in oral squamous cell carcinoma

Article | 更新时间：2025-12-31

- Mechanistic study on PLK4 regulation of invasion, proliferation and apoptosis in oral squamous cell carcinoma
- China Oncology Vol. 35, Issue 4, Pages: 365-375(2025)
- 作者机构：
  
  1. 山东第二医科大学附属医院口腔科，山东潍坊 261041
  2. 寿光市口腔医院，山东潍坊 262700
  3. 山东第二医科大学口腔医学院，山东潍坊 261053
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2025.04.004
  CLC：
- Received：24 October 2024，
  
  Revised：2025-02-10，
  
  Published：30 April 2025
- 稿件说明：
移动端阅览
Huan QIN, Jie WANG, Jie YANG, et al. Mechanistic study on PLK4 regulation of invasion, proliferation and apoptosis in oral squamous cell carcinoma[J]. China Oncology, 2025, 35(4): 365-375.
DOI：

Huan QIN, Jie WANG, Jie YANG, et al. Mechanistic study on PLK4 regulation of invasion, proliferation and apoptosis in oral squamous cell carcinoma[J]. China Oncology, 2025, 35(4): 365-375. DOI： 10.19401/j.cnki.1007-3639.2025.04.004.

摘要

背景与目的：

Polo样激酶4（Polo-like kinase 4，PLK4）为细胞周期调控蛋白，与多种恶性肿瘤的发生、发展关系密切。本研究旨在探究PLK4对口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）增殖、凋亡和侵袭的影响。

方法：

利用基于基因表达水平值的交互式分析平台2数据库（gene expression profiling interactive analysis 2，GEPIA2）和阿拉巴马大学伯明翰分校癌症数据分析门户网站数据库（the University of Alabama at Birmingham Cancer Data Analysis Portal，UALCAN）在线数据平台分析PLK4在头颈部鳞癌及周围正常组织中的表达，并分析OSCC细胞系中PLK4的mRNA表达和蛋白水平。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）检测进一步分析敲低和过表达PLK4后对磷脂酰肌醇3-激酶（phosphoinositide 3-kinase，PI3K）、磷酸化磷脂酰肌醇3-激酶（phosphorylated phosphoinositide 3-kinase，p-PI3K）、蛋白激酶B（protein kinase B，AKT）、磷酸化蛋白激酶B（phosphorylated protein kinase B，p-AKT）、生存素（survivin）、细胞周期蛋白依赖性激酶D1（cyclin D1）的mRNA表达和蛋白水平的影响。通过细胞计数试剂盒-8（cell counting kit-8，CCK-8）实验、流式细胞术、transwell侵袭实验分析PLK4对细胞的增殖、凋亡和侵袭活动的影响。此外，通过将12只4周龄SPF级BALB/c nude雌性裸鼠通过随机数字表法分为sh-NC组（

=6）和sh-PLK4组（

=6）。分别在裸鼠右前腋下注射sh-NC/sh-PLK4细胞进行裸鼠皮下移植瘤模型，观察统计两组裸鼠体质量、瘤体积和质量，并对剥离的瘤体组织进行H-E染色病理学诊断。动物实验已获得山东第二医科大学动物实验中心的批准（编号：2024SDL840）。

结果：

PLK4在OSCC中相较于正常组织呈现出高表达。此外，PLK4在OSCC细胞系（HN6、Cal-27、SCC-4、SCC-9、SCC-25）中相较于口腔黏膜上皮细胞高表达（

0.05）。Western blot结果显示，对OSCC细胞进行敲低和过表达PLK4后，PI3K/AKT信号转导通路蛋白p-PI3K、p-AKT、cyclin D1及survivin分别表达降低和增高（

0.05）；细胞增殖活力及穿膜细胞数在敲低和过表达PLK4后分别出现降低和增高，而细胞的凋亡率则分别增高和降低（

0.05）。此外，相较于sh-NC组，sh-PLK4组裸鼠肿瘤的体积和质量降低（

0.05），而两组裸鼠的质量差异无统计学意义（

0.05）。sh-PLK4组裸鼠肿瘤组织相较于sh-NC组

肿瘤组织核异形性减少。

结论：

Polo样激酶4可介导PI3K/AKT信号转导通路参与OSCC的侵袭、增殖和凋亡活动，有望成为治疗OSCC的新靶点。

Abstract

Background and purpose:

Polo-like kinase 4 (PLK4) is a cell cycle regulatory protein

which is closely related to the occurrence and development of a variety of malignant tumors. The aim of this study was to investigate the role of PLK4 in the proliferation

invasion and apoptosis of oral squamous cell carcinoma (OSCC).

Methods:

Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were used to analyze the expression of PLK4 in head and neck squamous cell carcinoma and surrounding normal tissues. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot were employed to evaluate the mRNA and protein expression of PLK4 in OSCC cells. We further analyzed PLK4

phosphoinositide 3-kinase (PI3K)

phosphorylated phosphoinositide 3-kinase (p-PI3K)

protein kinase B (AKT)

phosphorylated protein kinase B (p-AKT)

survivin

and cyclin D1 protein expression. The effects of PLK4 on cell proliferation

apoptosis and invasion were analyzed by cell counting kit-8 (CCK-8) assay

flow cytometry and transwell assay. In addition

12 4-week-old SPF BALB/c female nude mice were divided into sh-NC group (

=6) and sh-PLK4 group (

=6) by random number table method. The sh-NC/sh-PLK4 cells were injected into the right anterior armpit of nude mice for subcutaneous tumor formation. The body weight

tumor volume and tumor weight of the two groups of nude mice were observed

and the stripped tumor tissues were analyzed by H-E staining. The animal experiments were approved by the Animal Experiment Center of Shandong Second Medical University (No: 2024SDL840).

Results:

The results of GEPIA2 and UALCAN online databases showed that PLK4 was highly expressed in OSCC compared with normal t

issues. In addition

PLK4 was highly expressed in OSCC cell lines (HN6

Cal-27

SCC-4

SCC-9

SCC-25) compared with oral mucosal epithelial cells (

0.05). Western blot results showed that the expression levels of PI3K/AKT signaling pathway proteins p-PI3K

p-AKT

cyclin D1 and survivin were decreased after PLK4 knockdown and increased after PLK4 overexpression in OSCC cells (

0.05). The cell proliferation activity and the number of transmembrane cells were positively correlated with the decrease and increase of PLK4 expression (

0.05)

while the cell apoptotic rate was negatively correlated (

0.05)

indicating that cell proliferation and apoptosis were both affected. In addition

compared with the sh-NC group

the tumor volume and weight of the nude mice in the sh-PLK4 group were decreased (

0.05)

while there was no significant difference in the body weight of the nude mice between the two groups (

0.05). Moreover

the nuclear atypia of tumor tissues in sh-PLK4 group was lower than that in sh-NC group (

0.05).

Conclusion:

PLK4 can regulate the invasion

proliferation and apoptosis of OSCC cells

potentially through the activation of PI3K/AKT signaling pathway.

关键词

Keywords

references

梁壮 , 王伟 , 郭文博 , 等 . DPP3在口腔鳞状细胞癌中的表达及生物学作用 [J ] . 现代肿瘤医学 , 2024 , 32 ( 18 ): 3426 - 3433 .

LIANG Z , WANG W , GUO W B , et al . The expression and biological role of DPP3 in oral squamous cell carcinoma [J ] . J Mod Oncol , 2024 , 32 ( 18 ): 3426 - 3433 .

SAIKIA P J , PATHAK L , MITRA S , et al . The emerging role of oral microbiota in oral cancer initiation, progression and stemness [J ] . Front Immunol , 2023 , 14 : 1198269 .

SAIDAK Z , LAILLER C , TESTELIN S , et al . Contribution of genomics to the surgical management and study of oral cancer [J ] . Ann Surg Oncol , 2021 , 28 ( 11 ): 5842 - 5854 . DOI: 10.1245/s10434-021-09904-0 http://doi.org/10.1245/s10434-021-09904-0

NIU Q , SUN Q N , BAI R S , et al . Progress of nanomaterials-based photothermal therapy for oral squamous cell carcinoma [J ] . Int J Mol Sci , 2022 , 23 ( 18 ): 10428 .

LEI Q , YU Q W , YANG N , et al . Therapeutic potential of targeting polo-like kinase 4 [J ] . Eur J Med Chem , 2024 , 265 : 116115 .

CHAN C Y , YUEN V W , CHIU D K , et al . Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity [J ] . Hepatology , 2023 , 77 ( 3 ): 729 - 744 .

DENG S S , LU X L , ZHANG Z , et al . Identification and assessment of PLK1/2/3/4 in lung adenocarcinoma and lung squamous cell carcinoma: evidence from methylation profile [J ] . J Cell Mol Med , 2021 , 25 ( 14 ): 6652 - 6663 . DOI: 10.1111/jcmm.16668 http://doi.org/10.1111/jcmm.16668

PELLIZZARI S , BHAT V , ATHWAL H , et al . PLK4 as a potential target to enhance radiosensitivity in triple-negative breast cancer [J ] . Radiat Oncol , 2024 , 19 ( 1 ): 24 . DOI: 10.1186/s13014-024-02410-z http://doi.org/10.1186/s13014-024-02410-z

ZHAO Y , WANG X . PLK4: a promising target for cancer therapy [J ] . J Cancer Res Clin Oncol , 2019 , 145 ( 10 ): 2413 - 2422 . DOI: 10.1007/s00432-019-02994-0 http://doi.org/10.1007/s00432-019-02994-0

宋宁 , 李敏敏 , 郑文甜 , 等 . 突触融合蛋白结合蛋白4对口腔鳞状细胞癌细胞增殖和迁移的影响 [J ] . 中国病理生理杂志 , 2023 , 39 ( 8 ): 1390 - 1398 .

SONG N , LI M M , ZHENG W T , et al . Effects of syntaxin binding protein 4 on proliferation and migration of oral squamous cell carcinoma cells [J ] . Chin J Pathophysiol , 2023 , 39 ( 8 ): 1390 - 1398 .

CHEN Y F , HAN Z Y , ZHANG L , et al . TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma [J ] . J Transl Med , 2024 , 22 ( 1 ): 21 . DOI: 10.1186/s12967-023-04791-3 http://doi.org/10.1186/s12967-023-04791-3

GARVEY D R , CHHABRA G , NDIAYE M A , et al . Role of polo-like kinase 4 (PLK4) in epithelial cancers and recent progress in its small molecule targeting for cancer management [J ] . Mol Cancer Ther , 2021 , 20 ( 4 ): 632 - 640 . DOI: 10.1158/1535-7163.MCT-20-0741 http://doi.org/10.1158/1535-7163.MCT-20-0741

KRESSIN M , FIETZ D , BECKER S , et al . Modelling the functions of polo-like kinases in mice and their applications as cancer targets with a special focus on ovarian cancer [J ] . Cells , 2021 , 10 ( 5 ): 1176 .

FU F M , CHEN L K , YANG X H , et al . PLK4 is a key molecule in the formation of PGCCs and promotes invasion and migration of progeny cells derived from PGCCs [J ] . J Cancer , 2022 , 13 ( 9 ): 2954 - 2969 . DOI: 10.7150/jca.74211 http://doi.org/10.7150/jca.74211

张进忠 , 李悦淇 , 石科 , 等 . PLK4 基因在人食管鳞癌组织中的表达及对癌细胞增殖、侵袭迁移影响的研究 [J ] . 中国癌症杂志 , 2021 , 31 ( 12 ): 1185 - 1193 .

ZHANG J Z , LI Y Q , SHI K , et al . Expression and clinical significance of PLK4 gene in esophageal squamous cell carcinoma and its effect on cell proliferation, invasion and migration [J ] . China Oncol , 2021 , 31 ( 12 ): 1185 - 1193 .

ZHU W , XIE B . PLK4 inhibitor exhibits antitumor effect and synergizes sorafenib via arresting cell cycle and inactivating Wnt/β-catenin pathway in anaplastic thyroid cancer [J ] . Cancer Biol Ther , 2023 , 24 ( 1 ): 2223383.

HE Y , SUN M M , ZHANG G G , et al . Targeting PI3K/AKT signal transduction for cancer therapy [J ] . Signal Transduct Target Ther , 2021 , 6 ( 1 ): 425 .

XU P , HU K , ZHANG P , et al . Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis [J ] . Cancer Cell Int , 2022 , 22 ( 1 ): 13 . DOI: 10.1186/s12935-021-02368-y http://doi.org/10.1186/s12935-021-02368-y

MAO X Q , CHENG Y , ZHANG R Z , et al . RNA-seq and ATAC-seq analyses of multilineage differentiating stress enduring cells: comparison with dermal fibroblasts [J ] . Cell Biol Int , 2022 , 46 ( 9 ): 1480 - 1494 .

TANG W , JIA P , ZUO L , et al . Suppression of CX3CL1 by miR-497-5p inhibits cell growth and invasion through inactivating the ERK/AKT pathway in NSCLC cells [J ] . Cell Cycle , 2022 , 21 ( 16 ): 1697 - 1709 .

TUFAIL M , WAN W D , JIANG C H , et al . Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer [J ] . Chem Biol Interact , 2024 , 396 : 111055 .

GLAVIANO A , FOO A S C , LAM H Y , et al . PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer [J ] . Mol Cancer , 2023 , 22 ( 1 ): 138 . DOI: 10.1186/s12943-023-01827-6 http://doi.org/10.1186/s12943-023-01827-6

YU L , WEI J , LIU P D . Attacking the PI3K/AKT/mTOR signaling pathway for targeted therapeutic treatment in human cancer [J ] . Semin Cancer Biol , 2022 , 85 : 69 - 94 .

HE C P , CHEN Y T , ZHANG X M , et al . Down-regulation of ESRP2 inhibits breast cancer cell proliferation via inhibiting cyclinD1 [J ] . Sci Rep , 2024 , 14 ( 1 ): 28475 .

刘玉娟 , 郭明艳 . JMJD3 与 Cyclin D1 基因在喉鳞状细胞癌组织中的表达及意义 [J ] . 检验医学与临床 , 2023 , 20 ( 8 ): 1126 - 1129 .

LIU Y J , GUO M Y . Expressions and significance of JMJD3 and CyclinD1 in cancer tissues of laryngeal squamous cell carcinoma [J ] . Lab Med Clin , 2023 , 20 ( 8 ): 1126 - 1129 .

SIRAGUSA G , TOMASELLO L , GIORDANO C , et al . Survivin (BIRC5): implications in cancer therapy [J ] . Life Sci , 2024 , 350 : 122788.

Views

1123

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effects of NOL8 on cell proliferation, migration and invasion of oral squamous cell carcinoma

The influence ofPRUNE2 gene point mutation on proliferation, apoptosis, invasion and migration of prostate cancer DU145 cells

Mechanism of circular RNA hsa_circ_0012779 expression in nasopharyngeal carcinoma and its influence on cell biological behavior

Effect of tRF-Pro-CGG on the biological behavior of mouse pancreatic cancer cells and its molecular mechanism

Related Author

Xiaoxiao WANG

Xi CHEN

Minmin LI

Ning SONG

Dongyuan SUN

Yingying JIANG

曹达龙

朱文恺

Related Institution

School of Stomatology, Weifang Medical University

Department of Dentistry, Affiliated Hospital of Weifang Medical University

复旦大学附属肿瘤医院泌尿外科，复旦大学上海医学院肿瘤学系

厦门市第五医院神经外科

厦门大学医学院基础医学部

AI问答

⁰