B7-H6, an immunoligand for the natural killer cell activating receptor NKp30, reveals inhibitory effects on cell proliferation and migration, but not apoptosis, in cervical cancer derived-cell lines

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Abstract

Background

Although great progress has been made in treatment regimens, cervical cancer remains as one of the most common cancer in women worldwide. Studies focusing on molecules that regulate carcinogenesis may provide potential therapeutic strategies for cervical cancer. B7-H6, an activating immunoligand expressed by several tumor cells, is known to activate NK cell-mediated cytotoxicity once engaged with its natural receptor NKp30. However, the opposite, that is, the effects in the tumor cell triggered by B7-H6 after interacting with NKp30 has not yet been well explored.

Methods

In this study, we evaluated the surface expression of B7-H6 by flow cytometry. Later, we stimulated B7-H6 positive cervical cancer derived-cell lines (HeLa and SiHa) with recombinant soluble NKp30 (sNKp30) protein and evaluated biological effects using the impedance RTCA system for cell proliferation, the scratch method for cell migration, and flow cytometry for apoptosis. Cellular localization of B7-H6 was determined using confocal microscopy.

Results

Notably, we observed that the addition of sNKp30 to the cervical cancer cell lines decreased tumor cell proliferation and migration rate, but had no effect on apoptosis. We also found that B7-H6 is selectively maintained in tumor cell lines, and that efforts to sort and purify B7-H6 negative or positive cells were futile, as negative cells, when cultured, regained the expression of B7-H6 and B7-H6 positive cells, when sorted and cultivated, lost a percentage of B7-H6 expression.

Conclusions

Our results suggest that B7-H6 has an important, as of yet undescribed, role in the biology of the cervical tumor cells themselves, suggesting that this protein might be a promising target for anti-tumor therapy in the future.

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Most cited references 39

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Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis

Marc Arbyn, Elisabete Weiderpass, Laia Bruni … (2019)

Summary Background The knowledge that persistent human papillomavirus (HPV) infection is the main cause of cervical cancer has resulted in the development of prophylactic vaccines to prevent HPV infection and HPV assays that detect nucleic acids of the virus. WHO has launched a Global Initiative to scale up preventive, screening, and treatment interventions to eliminate cervical cancer as a public health problem during the 21st century. Therefore, our study aimed to assess the existing burden of cervical cancer as a baseline from which to assess the effect of this initiative. Methods For this worldwide analysis, we used data of cancer estimates from 185 countries from the Global Cancer Observatory 2018 database. We used a hierarchy of methods dependent on the availability and quality of the source information from population-based cancer registries to estimate incidence of cervical cancer. For estimation of cervical cancer mortality, we used the WHO mortality database. Countries were grouped in 21 subcontinents and were also categorised as high-resource or lower-resource countries, on the basis of their Human Development Index. We calculated the number of cervical cancer cases and deaths in a given country, directly age-standardised incidence and mortality rate of cervical cancer, indirectly standardised incidence ratio and mortality ratio, cumulative incidence and mortality rate, and average age at diagnosis. Findings Approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2·1 million cases), colorectal cancer (0·8 million) and lung cancer (0·7 million). The estimated age-standardised incidence of cervical cancer was 13·1 per 100 000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100 000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The highest incidence was estimated in Eswatini, with approximately 6·5% of women developing cervical cancer before age 75 years. China and India together contributed more than a third of the global cervical burden, with 106 000 cases in China and 97 000 cases in India, and 48 000 deaths in China and 60 000 deaths in India. Globally, the average age at diagnosis of cervical cancer was 53 years, ranging from 44 years (Vanuatu) to 68 years (Singapore). The global average age at death from cervical cancer was 59 years, ranging from 45 years (Vanuatu) to 76 years (Martinique). Cervical cancer ranked in the top three cancers affecting women younger than 45 years in 146 (79%) of 185 countries assessed. Interpretation Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in less-resourced countries. The global scale-up of HPV vaccination and HPV-based screening—including self-sampling—has potential to make cervical cancer a rare disease in the decades to come. Our study could help shape and monitor the initiative to eliminate cervical cancer as a major public health problem. Funding Belgian Foundation Against Cancer, DG Research and Innovation of the European Commission, and The Bill & Melinda Gates Foundation.

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Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

J Walboomers, M V Jacobs, M M Manos … (1999)

A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright 1999 John Wiley & Sons, Ltd.

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Revisiting the hallmarks of cancer.

Yousef Fouad, Carmen M Aanei (2017)

The hallmarks of cancer described by Hanahan and Weinberg have proved seminal in our understanding of cancer's common traits and in rational drug design. Not free of critique and with understanding of different aspects of tumorigenesis coming into clearer focus in the recent years, we attempt to draw a more organized and updated picture of the cancer hallmarks. We define seven hallmarks of cancer: selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation, while highlighting some considerations for the future of the field.

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Author and article information

Contributors

Susana del Toro-Arreola:

ORCID: http://orcid.org/0000-0003-4120-6796

susana@cucs.udg.mx

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 10 November 2020

Publication date PMC-release: 10 November 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 1083

Affiliations

[1 ]GRID grid.412890.6, ISNI 0000 0001 2158 0196, Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, , Universidad de Guadalajara, ; Sierra Mojada # 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico

[2 ]GRID grid.412890.6, ISNI 0000 0001 2158 0196, Laboratorio de Inmunología, Departamento de Fisiología, CUCS, , Universidad de Guadalajara, ; Guadalajara, Mexico

[3 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, Institute for Regenerative Cures, Department of Dermatology, , University of California-Davis, ; Davis, USA

[4 ]GRID grid.412890.6, ISNI 0000 0001 2158 0196, Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular, CUCBA, , Universidad de Guadalajara, ; Guadalajara, Mexico

[5 ]GRID grid.419157.f, ISNI 0000 0001 1091 9430, División de Inmunología, CIBO, , Instituto Mexicano del Seguro Social, ; Guadalajara, Mexico

[6 ]GRID grid.9486.3, ISNI 0000 0001 2159 0001, Centro de Física Aplicada y Tecnología Avanzada, , Universidad Nacional Autónoma de México, ; Querétaro, Mexico

[7 ]GRID grid.412858.2, ISNI 0000 0001 2164 1788, Unidad Académica de Ciencias Químico Biológicas y Farmacéuticas, , Universidad Autónoma de Nayarit, ; Tepic, Mexico

Author information

Susana del Toro-Arreola http://orcid.org/0000-0003-4120-6796

Article

Publisher ID: 7608

DOI: 10.1186/s12885-020-07608-4

PMC ID: 7654602

PubMed ID: 33172426

SO-VID: a70aae0f-4e16-42b7-9f63-1b3018f52724

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 24 May 2020

Date accepted : 31 October 2020

Funding

Funded by: Consejo Nacional de Ciencia y Tecnología (CONACYT)

Award ID: PN-2015-993

Award ID: 2017-290195

Funded by: Universidad de Guadalajara

Award ID: REC/CINV/RG/025/2019

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cervical cancer,b7-h6,b7h6,cell proliferation,cell migration,apoptosis

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cervical cancer, b7-h6, b7h6, cell proliferation, cell migration, apoptosis

B7-H6, an immunoligand for the natural killer cell activating receptor NKp30, reveals inhibitory effects on cell proliferation and migration, but not apoptosis, in cervical cancer derived-cell lines

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Karger: Oncology

Most cited references 39

Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

Revisiting the hallmarks of cancer.

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