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Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells

Cellular Oncology volume 45, pages 85–101 (2022)Cite this article

Abstract

Purpose

Obesity is as an important risk factor and has been associated with a worse prognosis in at least 13 distinct tumor types. This is partially due to intercellular communication between tumor cells and adipose tissue-derived stem cells (ADSCs), which are increased in obese individuals. As yet, however, little is known about the molecular changes occurring in ADSCs in these conditions. Cervical cancer has a high incidence and mortality rate in women from developing countries, particularly in those with a high body mass index (BMI).

Methods

We analyzed the expression profile of ADSCs co-cultured with cervical cancer cells through massive RNA sequencing followed by evaluation of various functional alterations resulting from the modified transcriptome.

Results

A total of 761 coding and non-coding dysregulated RNAs were identified in ADSCs after co-culture with HeLa cells (validation in CaSki and SiHA cells). Subsequent network analysis showed that these changes were correlated with migration, stemness, DNA repair and cytokine production. Functional experiments revealed a larger ALDHhigh subpopulation and a higher migrative capacity of ADSCs after co-culture with HeLa cells. Interestingly, CXCL3 and its intragenic long-noncoding RNA, lnc-CXCL3, were found to be co-regulated during co-culture. A loss-of-function assay revealed that lnc-CXCL3 acts as a key regulator of CXCL3 expression.

Conclusions

Our results suggest that intercellular communication between ADSCs and cervical cancer cells modifies the RNA expression profile in the former, including that of lncRNAs, which in turn can regulate the expression of diverse chemokines that favor malignancy-associated capacities such as migration.

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Data availability

The data obtained from the sequencing were deposited: SRA data: PRJNA780960.

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Acknowledgements

This work was part of the PhD thesis of Marcela Angelica De la Fuente Hernandez (CVU: 441075) from the Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM). The work was supported by a Consejo Nacional de Ciencia y Tecnologia (CONACyT) fellowship (Registry number 270150). We thank Dr. Alfredo Mendoza for his help in transcriptome sequencing (Unit of Sequencing Genomics, Instituto Nacional de Medicina Genomica, Mexico City), M.C. Linda Nelly Patiño for her help in the cytometry experiments (Unit of Citometry, Instituto Nacional de Medicina Genómica, Mexico City), M.C. Miguel Angel Sarabia Sanchez for his help in the cytometry experiments in the Laboratorio Nacional de Citometría de Flujo (LabNalCit), Mexico City and Dr. Daniel Díaz for his kind assistance in proofreading this manuscript.

Funding

Marcela Angelica De la Fuente Hernandez is a doctoral student from Programa de Doctorado en Ciencias Biologicas, Universidad Nacional Autonoma de México (UNAM) and received a fellowship 270150 from CONACyT. This work was supported by grant A1-S-33543 CONACyT to Vilma Maldonado.

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Authors and Affiliations

  1. Facultad de Medicina, Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico (UNAM), Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacan, Mexico City, Mexico

    Marcela Angelica De la Fuente-Hernandez & Vilma Maldonado Lagunas

  2. Epigenetics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periferico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P, 14610, Mexico City, Mexico

    Marcela Angelica De la Fuente-Hernandez, Erika Claudia Alanis-Manriquez, Karla Vazquez-Santillan & Vilma Maldonado Lagunas

  3. Gastrosurgery Service, UMAE. Hospital de Especialidades Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico

    Eduardo Ferat-Osorio & Arturo Rodriguez-Gonzalez

  4. Unidad de Investigacion Medica en Inmunoquimica. Hospital de Especialidades, Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico

    Lourdes Arriaga-Pizano

  5. Functional Cancer Genomics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periférico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P., 14610, Mexico City, Mexico

    Jorge Melendez-Zajgla

  6. National Cancer Institute, San Fernando 22, Seccion XVI, Tlalpan, Mexico City, Mexico

    Veronica Fragoso-Ontiveros & Rosa Maria Alvarez-Gomez

Authors
  1. Marcela Angelica De la Fuente-Hernandez
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  2. Erika Claudia Alanis-Manriquez
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  3. Eduardo Ferat-Osorio
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  4. Arturo Rodriguez-Gonzalez
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  5. Lourdes Arriaga-Pizano
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  6. Karla Vazquez-Santillan
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  7. Jorge Melendez-Zajgla
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  8. Veronica Fragoso-Ontiveros
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  9. Rosa Maria Alvarez-Gomez
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  10. Vilma Maldonado Lagunas
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Contributions

MDH: substantial contributions to the conception and design of the study; substantial contributions to data acquisition and analysis and drafting the article. EAM: established the primary culture. EFO: contributed to the selection and enrollment of patients for obtaining visceral adipose tissue. ARG: contributed to the selection and enrollment of patients for obtaining visceral adipose tissue. LAP: contributed to the revision of the manuscript. KVS: contributed to the GSEA analysis of the RNAseq data. JMZ: made substantial contributions to the analysis and interpretation of sequencing data. VFO: contributed to the revision of the manuscript. RMAG: Contributed to the revision of the manuscript. VML: made substantial contributions to the conception and design of the study, coordinated the work, analyzed the data and contributed to the manuscript draft.

Corresponding author

Correspondence to Vilma Maldonado Lagunas.

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Ethical approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and consent to participate.

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Not applicable. Inthe manuscript, no data is handled that puts the identity or privacy of the donor at risk.

Competing interests

The authors declare that there is no conflict of interest.

Research involving human participants

Morbidly obese women undergoing gastric bypass donor visceral adipose tissue.

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Informed consent was obtained from all individual participants included in the study.

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De la Fuente-Hernandez, M.A., Alanis-Manriquez, E.C., Ferat-Osorio, E. et al. Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells. Cell Oncol. 45, 85–101 (2022). https://doi.org/10.1007/s13402-021-00653-6

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Keywords

  • Cervical cancer
  • Obesity
  • ADSC
  • HeLa
  • Transcriptome
  • lncRNA
  • Intercellular communication