Evaluating the role of PLGF and VEGFR-1/ Flt-1 in the development of cervical intraepithelial neoplasia and invasive cervical carcinoma in the background of HIV infection in women living in South Africa

Cervical cancer remains a major public health challenge in sub-Saharan Africa, where high-risk human papillomavirus (hr-HPV) infection and HIV co-morbidity drive elevated incidence and mortality (Kelly et al., 2022). While persistent hr-HPV infection is the primary etiological factor, the molecular mechanisms underlying progression from low-grade squamous intraepithelial lesions (LSIL) to high grade intraepithelial lesions (HSIL) and invasive carcinoma remain incompletely understood. Angiogenesis within the tumour microenvironment, mediated by placental growth factor (PLGF) and its receptor vascular endothelial growth receptor (VEGFR1/Flt-1), has been implicated in cervical carcinogenesis, yet their expression patterns across lesions to disease are poorly characterised. This study evaluated the expression patterns of PLGF and its receptor VEGFR1/Flt-1 across cervical intraepithelial lesion grades and invasive cancer. This retrospective, laboratory-based study evaluated the utility of PLGF and VEGFR1/Flt-1 as biomarkers across the spectrum of cervical intraepithelial neoplasia (CIN) to invasive carcinoma in a cohort of South African women, stratified by HIV status. Expression was evaluated at transcript and protein levels in formalin fixed paraffin-embedded cervical tissue, plasma and peripheral blood mononuclear cells (PBMCs) from 80 women diagnosed with LSIL, HSIL, squamous cell carcinoma (SCC) or adenocarcinoma (ADC). High-risk HPV genotyping was performed using the AmpFire HR-HPV genotyping assay, PLGF and VEGFR1/Flt-1 mRNA expression and protein levels were respectively quantified by Taqman quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Protein expression and location was also assessed via immunohistochemistry (IHC). The prevalence of HR-HPV was 75%, with higher infection rates and multiple genotype co-infections among HIV positive women. ELISA analysis revealed low plasma PLGF concentrations, with LSIL samples ranging from 7.0 pg/mL to 30.6 pg/mL, HSIL from 3.5 pg/mL to 63.4 pg/mL, SCC from 0.4 pg/mL to 142.0 pg/mL and ADC from 0.2 pg/mL to 4.2 pg/mL. VEGFR1/Flt-1 concentrations were markedly higher than PLGF, with LSIL ranging from 193.5 pg/mL to 301.7 pg/mL, HSIL from 80.0 pg/mL to 906.5 pg/mL, SCC from 32.0 pg/mL to 356.9 pg/mL, and ADC from 132.3 pg/mL to 196.3 pg/mL. One-way ANOVA indicated significant differences between diagnostic groups for PLGF and VEGFR1/Flt-1. IHC confirmed strong VEGFR1/Flt-1 staining intensity from LSIL to SCC, whereas PLGF staining was weaker and scattered, suggesting localised activity of PLGF signaling pathway within specific epithelial or stromal regions or of PLGF in cellular populations, possibly reflecting stromal remodelling processes rather than widespread expression. qPCR analysis of 15 paired PLGF-positive and VEGFR1/Flt-1-positive (PLGF+/ VEGFR1/Flt-1 +) samples showed no significant differences in PLGF transcript levels, while VEGFR1/Flt-1 mRNA was significantly upregulated across diagnostic categories. The median VEGFR1/Flt-1 transcript expression was higher in LSIL and SCC compared to HSIL. Collectively, these findings align with that of Yang et al. (2020) and suggest that VEGFR1/Flt-1 have the potential to serve as a biomarker for angiogenic activation for progression to cervical cancer. Whereas PLGF exhibited limited expression and variable transcripts levels. Future studies with larger cohorts are needed to evaluate these trends and their potential to serve as biomarkers.

Grantor dc:publisher

Stellenbosch : Stellenbosch University

Year dc:date.issued

2026

Author dc:creator

• Walters, Tasha-Leigh

Advisors dc:contributor.advisor

• Coetzee, Liezel
• Sibeko, Singeziwe
• Sanderson-November, Micheline

Language dc:language.iso

en

Repository record dc:identifier.uri

https://scholar.sun.ac.za/handle/10019.1/135570

OAI identifier oai:identifier

oai:scholar.sun.ac.za:10019.1/135570