Targeted Inhibition of p21 Promotes the Growth of Breast Cancer Cells and Impairs the Tumor-Killing Effect of the Vaccinia Virus.

IF 2.2 4区 医学 Q3 ONCOLOGY Journal of Breast Cancer Pub Date : 2024-10-01 Epub Date: 2024-09-02 DOI:10.4048/jbc.2024.0063
Xiaoyuan Jia, Yujia Zhao, Qiang Li, Xiaming Lu, Xiaoyan Wang, Hui Wang, Ziyi Shi, Yipeng Xu, Biao Huang, Fang Huang, Yigang Wang
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Abstract

Purpose: Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus.

Methods: p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumor-killing effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts.

Results: p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDA-MB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells.

Conclusion: Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.

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靶向抑制 p21 会促进乳腺癌细胞的生长并削弱疫苗病毒的杀瘤效果
目的:疫苗病毒被广泛用作人类癌症治疗的溶瘤剂,几种版本的疫苗病毒已在乳腺癌中显示出强大的抗肿瘤效果。大多数疫苗病毒都经过胸苷激酶(TK)缺失修饰。细胞周期蛋白依赖性激酶抑制剂 p21 在乳腺癌中的功能仍存在争议。方法:制备 p21 KD MDA-MB-231 和 p21 KD MCF-7 细胞,使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)和划痕愈合试验评估细胞增殖和迁移率。在小鼠模型中,比较了 p21KD MDA-MB-231 细胞和对照细胞异种移植的肿瘤生长情况。此外,还使用低熔琼脂糖和无血清培养法测定了 p21KD 乳腺癌细胞的集落形成和球形成能力。结果:p21 KD 增加了 MDA-MB-231 和 MCF-7 细胞的生长和迁移,促进了 MDA-MB-231 细胞在小鼠体内的生长,同时降低了集落形成和球形成能力。p21 KD MDA-MB-231 细胞中 TK 的表达减少。野生型和缺失 TK 的疫苗病毒在 p21KD MDA-MB-231 细胞中的溶瘤作用均减弱。TK缺失的疫苗病毒对携带p21 KD MDA-MB-231细胞的异种移植小鼠的肿瘤杀伤作用也有所减弱:结论:靶向抑制 p21 会加速乳腺癌细胞的增殖和迁移,并削弱疫苗病毒的杀瘤效果,这表明癌细胞中的 p21 水平会干扰疫苗病毒溶瘤疗法。
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来源期刊
Journal of Breast Cancer
Journal of Breast Cancer 医学-肿瘤学
CiteScore
3.80
自引率
4.20%
发文量
43
审稿时长
6-12 weeks
期刊介绍: The Journal of Breast Cancer (abbreviated as ''J Breast Cancer'') is the official journal of the Korean Breast Cancer Society, which is issued quarterly in the last day of March, June, September, and December each year since 1998. All the contents of the Journal is available online at the official journal website (http://ejbc.kr) under open access policy. The journal aims to provide a forum for the academic communication between medical doctors, basic science researchers, and health care professionals to be interested in breast cancer. To get this aim, we publish original investigations, review articles, brief communications including case reports, editorial opinions on the topics of importance to breast cancer, and welcome new research findings and epidemiological studies, especially when they contain a regional data to grab the international reader''s interest. Although the journal is mainly dealing with the issues of breast cancer, rare cases among benign breast diseases or evidence-based scientifically written articles providing useful information for clinical practice can be published as well.
期刊最新文献
Variability in Breast Density Estimation and Its Impact on Breast Cancer Risk Assessment. p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis. Targeted Inhibition of p21 Promotes the Growth of Breast Cancer Cells and Impairs the Tumor-Killing Effect of the Vaccinia Virus. Histopathological Downgrading of Borderline Phyllodes Tumor in a Young Patient Following Chemotherapy: A Case Report. Risk of Lymphedema After Sentinel Node Biopsy in Patients With Breast Cancer.
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