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Upregulation of MTA1 expression by human papillomavirus infection promotes CDDP resistance in cervical cancer cells via modulation of NF-κB/APOBEC3B cascade

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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

We are grateful to Ms. Hui Wang (Department of Medical Psychology, Fourth Military Medical University, Xi’an, 710032, China) for her helpful advice and discussion regarding the possible functions of MTA1.

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Author notes

  1. Qiu-ping Jia and Chang-you Yan contributed equally to this work.

Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, The 2nd Affiliated Hospital of Xi’an Medical University, No. 167 Fangdong Road, Xi’an, 710038, Shaanxi, People’s Republic of China

    Qiu-ping Jia & Lei Cao

  2. Family Planning Service Stations of Health and Family Planning Commission of Chengcheng County, Chengcheng County, Weinan, 714000, Shaanxi, China

    Chang-you Yan

  3. Department of Gynaecology and Obstetrics, The 1st Affiliated Hospital of Xi’an Medical University, Xi’an, 710038, Shaanxi, People’s Republic of China

    Xue-rong Zheng

  4. Department of Gynaecology and Obstetrics, XD Group Hospital, Xi’an, 710077, Shaanxi, People’s Republic of China

    Xia Pan & Xin Cao

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  1. Qiu-ping Jia
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Correspondence to Lei Cao.

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Conflict of interest

Qiu-ping Jia declares that she has no conflict of interest. Chang-you Yan declares that he has no conflict of interest. Xue-rong Zheng declares that she has no conflict of interest. Xia Pan declares that she has no conflict of interest. Xin Cao declares that she has no conflict of interest. Lei Cao declares that she has no conflict of interest.

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Supplementary Fig. 1

MTA1 acts upstream of APOBEC3B signaling, and the regulation of APOBEC3B expression by MTA1 is dependent on the NF-κB pathway in CCa cells. (A, B) HeLa and SiHa cells were transfected with pCMV6-XL5-MTA1 or empty vector using Lipofectamine 2000. 48 h later, cells were harvested and were then incubated with 5 μM of parthenolide for another 6h, followed by RT-qPCR analysis of the expression levels of MTA1 and APOBEC3B transcripts in both cell types (*P<0.05; **P<0.01). (C, D) HeLa and SiHa cells were transfected with pCMV6-APOBEC3B or empty vector using Lipofectamine 2000. 48 h later, cells were harvested and subjected to RT-qPCR analysis of the expression levels of MTA1 and APOBEC3B transcripts in both cell types (*P<0.05; **P<0.01) (PPTX 81 KB)

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Jia, Qp., Yan, Cy., Zheng, Xr. et al. Upregulation of MTA1 expression by human papillomavirus infection promotes CDDP resistance in cervical cancer cells via modulation of NF-κB/APOBEC3B cascade. Cancer Chemother Pharmacol 83, 625–637 (2019). https://doi.org/10.1007/s00280-018-03766-2

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  • DOI: https://doi.org/10.1007/s00280-018-03766-2

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