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Expression of miR-34a and miR-15b during the progression of cervical cancer in a murine model expressing the HPV16 E7 oncoprotein

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Abstract

The high-risk human papillomavirus (HR-HPV) E7 oncoprotein appears to be a major determinant for cell immortalization and transformation altering critical processes such as cell proliferation, apoptosis, and immune response. This oncoprotein plays an essential role in cervical carcinogenesis, but other cofactors such as long-term use of hormonal contraceptives are necessary to modulate the risk of cervical cancer (CC). The role of HR-HPVs in the alteration of microRNA (miRNA) levels in persistent viral infections currently remains unclear. The aim of this study was to evaluate the miR-34a and miR-15b expression levels in the murine HPV16K14E7 (K14E7) transgenic model after chronic estrogen (E2) treatment and their involvement in CC. Interestingly, results showed that, although miR-34a expression is elevated by the HPVE7 oncogene, this expression was downregulated in the presence of both the E7 oncoprotein and chronic E2 in cervical carcinoma. On the other hand, miR-15b expression was upregulated along cervical carcinogenesis mainly by the effect of E2. These different changes in the expression levels of miR-34a and miR-15b along cervical carcinogenesis conduced to low apoptosis levels, high cell proliferation and finally, to cancerous cervical tissue development. In this work, we also determined the relative mRNA expression of Cyclin E2 (Ccne2), Cyclin A2 (Ccna2), and B cell lymphoma 2 (Bcl-2) (target genes of miR-34a and miR-15b); Sirtuin 1 (Sirt1), Cmyc, and Bax (miR-34a target genes); and p21/WAF1 (mir15b target gene) and the H-ras oncogene. Given the modifications in the expression levels of miR-34a and miR-15b during the development of cervical cancer, it will be useful to carry out further investigation to confirm them as molecular biomarkers of cancer.

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Acknowledgements

We are grateful to Mr. Lauro Macías, Dr. Jorge Fernández-Hernández, Dr. Ricardo Gaxiola-Centeno, Dr. Benjamin Chávez-Álvarez, and Dr. Rafael Leyva-Muñoz (CINVESTAV-IPN, México) for excellent technical support.

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Funding

This work was supported by Consejo Nacional de Ciencia y Tecnologia (CONACyT-Mexico; grant number: 0201904).

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Authors and Affiliations

  1. Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del IPN, Av. IPN 2508, Colonia San Pedro Zacatenco Delegación Gustavo A. Madero, 07360, Mexico City, CP, Mexico

    Rodolfo Ocadiz-Delgado, Jose-Luis Cruz-Colin, Elizabeth Alvarez-Rios, Antonio Torres-Carrillo, Karina Hernandez-Mendoza, Juan-Cristobal Conde-Pérezprina, Guadalupe-Isabel Dominguez-Gomez, Enrique Garcia-Villa & Patricio Gariglio

  2. Department of Genomic Diagnostic, INMEGEN, Mexico City, Mexico, Mexico

    Jose-Luis Cruz-Colin

  3. Subdirección de Investigación Clínica, INCan, Mexico City, Mexico, Mexico

    Guadalupe-Isabel Dominguez-Gomez

  4. McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI, USA

    Paul F. Lambert

Authors
  1. Rodolfo Ocadiz-Delgado
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  2. Jose-Luis Cruz-Colin
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  3. Elizabeth Alvarez-Rios
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  8. Enrique Garcia-Villa
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  9. Paul F. Lambert
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  10. Patricio Gariglio
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Contributions

All authors contributed to the study conception and design. Rodolfo Ocadiz-Delgado, Patricio Gariglio, Elizabeth Alvarez-Rios, and Enrique García-Villa contributed to data collection and analysis. Material preparation and experimental procedures were performed by Rodolfo Ocadiz-Delgado, Jose-Luis Cruz-Colin, Antonio Torres-Carrillo, Karina Hernandez-Mendoza, Juan-Cristobal Conde-Pérezprina and Guadalupe-Isabel Dominguez-Gomez. The first draft of the manuscript was written by Rodolfo Ocadiz-Delgado, Paul F Lambert and Patricio Gariglio. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Patricio Gariglio.

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The authors declare no competing interests.

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All mouse procedures were approved by the Research Unit for Laboratory Animal Care Committee (UPEAL-CINVESTAV-IPN, Mexico; NOM-062-ZOO-1999).

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Key Points -miR-34a is downregulated by HPVE7 oncoprotein and E2 in cervical carcinoma-miR-15b is upregulated in cervical carcinogenesis by E2-miR-34a and miR-15b expression levels could be useful as cervical cancer biomarkers

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Ocadiz-Delgado, R., Cruz-Colin, JL., Alvarez-Rios, E. et al. Expression of miR-34a and miR-15b during the progression of cervical cancer in a murine model expressing the HPV16 E7 oncoprotein. J Physiol Biochem 77, 547–555 (2021). https://doi.org/10.1007/s13105-021-00818-9

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