Upregulation of MTA1 expression by human papillomavirus infection promotes CDDP resistance in cervical cancer cells via modulation of NF-κB/APOBEC3B cascade
| Autor: | Xin Cao, Lei Cao, Qiu-ping Jia, Xue-rong Zheng, Chang-You Yan, Xia Pan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Mice Nude Uterine Cervical Neoplasms Antineoplastic Agents Toxicology Minor Histocompatibility Antigens 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Cytidine Deaminase medicine Animals Humans Pharmacology (medical) Viability assay Pharmacology Cisplatin Gene knockdown Mice Inbred BALB C Cytosine deaminase Papillomavirus Infections NF-kappa B NF-κB Oncogene Proteins Viral Xenograft Model Antitumor Assays Up-Regulation DNA-Binding Proteins Repressor Proteins 030104 developmental biology Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Cancer research Trans-Activators Female Chromatin immunoprecipitation medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 83(4) |
| ISSN: | 1432-0843 |
| Popis: | Compelling evidence establishes the etiological role of viral proteins E6 and E7 of high-risk human papillomaviruses (HPV) in cervical carcinogenesis, but their contribution in chemoresistance that leads to advanced metastatic lesions remains poorly defined. Since metastasis-associated protein 1 (MTA1) upregulation and augmentation of APOBEC3B expression are both strongly associated with cervical cancer (CCa) development, and both molecules have been shown to be functionally associated with NF-κB pathway, we therefore sought to investigate the potential mechanistic link between MTA1, APOBEC3B and NF-κB during the pathogenesis of cisplatin (CDDP) resistance in HPV-positive CCa cells. MTA1 expression was assessed in HPV-transfected CCa cells using quantitative RT-PCR and immunoblotting. Effects of MTA1 deregulation on CDDP chemosensitivity in CCa cells were determined by measuring cell viability, apoptosis and in vivo oncogenic capacity. Finally, we studied the transcriptional regulation of the antiviral DNA cytosine deaminase APOBEC3B by MTA1 using multiple approaches including DNA deaminase activity assay, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation and transient/stable transfection, at the molecular and functional levels. Expression levels of MTA1 were significantly induced in HPV-positive CCa cells. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause MTA1 upregulation. Moreover, MTA1 knockdown potentiated CDDP sensitivity in highly metastatic CCa cells. Mechanistically, MTA1 acted as an indirect upstream modulator of APOBEC3B transcription during the pathogenesis of CDDP chemoresistance. HPV-mediated stimulation of APOBEC3B expression was accompanied by the enhanced recruitment of Iκκ α/β and p65 to the NF-κB consensus sites in the APOBEC3B promoter, and this recruitment was substantially abrogated by MTA1 siRNA treatment. These findings reveal an obligatory coregulatory role of MTA1 in the indirect regulation of APOBEC3B expression via classical NF-κB pathway, and also suggest that inhibition of MTA1/NF-κB/APOBEC3B cascade may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes from CDDP resistance in CCa. |
| Databáze: | OpenAIRE |
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