TOP2A Promotes Cell Migration, Invasion and Epithelial–Mesenchymal Transition in Cervical Cancer via Activating the PI3K/AKT Signaling

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Abstract

Background/Objective

Topoisomerases type IIA (TOP2A) was identified to present with a high-expression pattern in cervical cancer. However, TOP2A role in the progression of cervical cancer remains unknown. Here, we aimed to explore the effect and reveal the underlying mechanism of TOP2A in the migration, invasion and epithelial–mesenchymal transition (EMT) of cervical cancer.

Materials and Methods

The expression profiles of TOP2A in 20 paired cervical cancer tissues and the paracancerous normal tissues were detected by using Western blotting assay. Transwell chambers were used to test cell migration and invasion abilities. Cell morphology and the expressions of E-cadherin and N-cadherin were detected to assess cell EMT. LY294002 was used to inhibit the activation of PI3K/AKT signaling.

Results

Compared with the paracancerous normal tissues, TOP2A was overexpressed in 85% (17/20) cervical cancer tissues. Repression of TOP2A expression in SiHa cells significantly weakened cell migration and invasion abilities, reduced cell numbers in shuttle shape and increased E-cadherin expression while decreased E-cadherin expression. To the opposite, overexpression of TOP2A in Hela cells induced opposite results. In addition, the expression of p-AKT was increased when TOP2A was overexpressed in Hela cells, and p-AKT expression was decreased when TOP2A was silenced in SiHa cells. Moreover, suppression of the PI3K/AKT signaling with LY294002 treatment apparently rescued TOP2A-mediated promotions in cell migration, invasion and EMT in Hela cells.

Conclusion

This study reveals that TOP2A is abnormally overexpressed in cervical cancer tissues, and TOP2A overexpression leads to cell migration, invasion and EMT via activating PI3K/AKT signaling.

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Most cited references 18

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Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study.

M H Stoler, Rhett Schiffman, (2001)

Despite a critical presumption of reliability, standards of interpathologist agreement have not been well defined for interpretation of cervical pathology specimens. To determine the reproducibility of cytologic, colposcopic histologic, and loop electrosurgical excision procedure (LEEP) histologic cervical specimen interpretations among multiple well-trained observers. The Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS), an ongoing US multicenter clinical trial. From women enrolled in ALTS during 1996-1998, 4948 monolayer cytologic slides, 2237 colposcopic biopsies, and 535 LEEP specimens were interpreted by 7 clinical center and 4 Pathology Quality Control Group (QC) pathologists. kappa Values calculated for comparison of the original clinical center interpretation and the first QC reviewer's masked interpretation of specimens. For all 3 specimen types, the clinical center pathologists rendered significantly more severe interpretations than did reviewing QC pathologists. The reproducibility of monolayer cytologic interpretations was moderate (kappa = 0.46; 95% confidence interval [CI], 0.44-0.48) and equivalent to the reproducibility of punch biopsy histopathologic interpretations (kappa = 0.46; 95% CI, 0.43-0.49) and LEEP histopathologic interpretations (kappa = 0.49; 95% CI, 0.44-0.55). The lack of reproducibility of histopathology was most evident for less severe interpretations. Interpretive variability is substantial for all types of cervical specimens. Histopathology of cervical biopsies is not more reproducible than monolayer cytology, and even the interpretation of LEEP results is variable. Given the degree of irreproducibility that exists among well-trained pathologists, realistic performance expectations should guide use of their interpretations.

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TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

David Labbé, Christopher Sweeney, Myles Brown … (2017)

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines.Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR.

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Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A

Rui Zhang, Jian Xu, Jian Zhao … (2018)

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Manag Res

Journal ID (iso-abbrev): Cancer Manag Res

Journal ID (publisher-id): CMAR

Journal ID (pmc): cancmanres

Title: Cancer Management and Research

Publisher: Dove

ISSN (Electronic): 1179-1322

Publication date (Electronic): 21 May 2020

Publication date Collection: 2020

Volume: 12

Pages: 3807-3814

Affiliations

[1 ]Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China

[2 ]Department of Paediatrics, Maternal and Child Health Hospital of Guiyang City , Guiyang, Guizhou, People’s Republic of China

[3 ]Department of Interventional Radiology, The Affiliated Baiyun Hospital of Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China

[4 ]Department of Oncology, The Second Affiliated Hospital of Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China

[5 ]Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China

[6 ]Guiyang Customs Guizhou International Travel Healthcare Center , Guiyang, Guizhou, People’s Republic of China

[7 ]Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China

Author notes

Correspondence: Fenghu Li Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University , Guiyang City, Guizhou Province, People’s Republic of China Email fenghuli19@163.com

Zhi Huang Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University , Guiyang City, Guizhou Province, People’s Republic of China Email doctor@huangzhi.com

[*]

These authors contributed equally to this work

Author information

Zhi Huang http://orcid.org/0000-0001-9020-897X

Article

Publisher ID: 240577

DOI: 10.2147/CMAR.S240577

PMC ID: 7251484

PubMed ID: 32547216

SO-VID: a890fc40-802d-4809-966c-063226e7817f

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 01 December 2019

Date accepted : 22 April 2020

Page count

Figures: 5, Tables: 1, References: 32, Pages: 8

Funding

Funded by: the Project of Guiyang Municipal Science and Technology Bureau

Funded by: Guizhou education department youth science and technology talent growth program

Funded by: Guiyang science and technology bureau big health science and technology cooperation

Funded by: Guiyang baiyun district science and technology bureau

This study is supported by the following foundations, the Project of Guiyang Municipal Science and Technology Bureau (No.: Zhu Ke [2018] 1–37), Guizhou education department youth science and technology talent growth program (No. KY [2015] 159), Guizhou medical university 2017 academic new seedling cultivation and innovation exploration special plan (No. [2017] 5718), Guiyang science and technology bureau big health science and technology cooperation (No. [2018] 1–76), and Guiyang baiyun district science and technology bureau (No. [2017] 5718).

TOP2A Promotes Cell Migration, Invasion and Epithelial–Mesenchymal Transition in Cervical Cancer via Activating the PI3K/AKT Signaling

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Abstract

Background/Objective

Materials and Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 18

Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study.

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A

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