Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT

Autor: Wei Duan, Dan Zi, Shu Nan Wang, Qing Li, Dong Wang, Meng Sheng Deng, Guanbin Song, Cheng Yuan Qian, Kenneth D. Westover, Cheng Xiong Xu, Zhi Wei Zhou, Jian-Min Wang, Cheng Yi Mao
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Epithelial-Mesenchymal Transition
Uterine Cervical Neoplasms
Transfection
Metastasis
Mice
03 medical and health sciences
0302 clinical medicine
Antigens
CD
DNA-(Apurinic or Apyrimidinic Site) Lyase
medicine
ZEB1
Animals
Humans
Epithelial–mesenchymal transition
Neoplasm Metastasis
Lymph node
RC254-282
Cervical cancer
Cadherin
business.industry
Research
EMT
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
E-cadherin
Zinc Finger E-box-Binding Homeobox 1
Middle Aged
Cadherins
medicine.disease
030104 developmental biology
medicine.anatomical_structure
Oncology
APE1
Lymphatic Metastasis
030220 oncology & carcinogenesis
Cancer research
Cervical cancer metastasis
Heterografts
Immunohistochemistry
Female
Ectopic expression
Signal transduction
business
Oxidation-Reduction
HeLa Cells
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-13 (2021)
ISSN: 1756-9966
DOI: 10.1186/s13046-021-02006-5
Popis: Background Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. Methods We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. Results Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. Conclusion Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.
Databáze: OpenAIRE
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