Cell signalling of the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) axis in HIV associated pre-eclampsia.
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Date
2021
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Abstract
Background: Epidermal growth factor is a protein which, when bound to epidermal growth
factor receptor, facilitates cell proliferation and differentiation, hence is vital for a successful
normal pregnancy. In preeclampsia (PE), EGFR signalling is dysregulated leading to decline in
blood flow to the fetus. Furthermore, aberrant EGF/EGFR signalling leads to deficient
trophoblast development. The Trans-Activator of transcription (Tat) protein, displayed in HIV
inhibits EGF related processes. Since PE and HIV infection are the leading causes of both
maternal morbidity and mortality in South Africa; this study focuses on examining EGF/EGFR
signalling in HIV associated PE and their effect on downstream targets.
Methods: Post ethics approval; this study selected 80 pregnant women from an archive of
retrospectively stored serum samples. The samples were stratified by type of pregnancy and
HIV status into the following groups: a) HIV negative preeclamptic women (n=20), b) HIV
positive preeclamptic women (n=20), c) HIV negative normotensive pregnant women (n=20)
and d) HIV positive normotensive pregnant women (n=20). Both EGF and EGFR were
multiplexed in a Bioplex immunoassay technique to determine their serum concentration across
study groups at term.
Results: Based on the clinical data, statistically significant differences were obtained across
groups for gestational age (p < 0.001), birth weight (p < 0.001), systolic BP (p < 0.001), BMI (p
= 0.048), diastolic BP (p < 0.001) and maternal weight (p = 0.002). However, no statistical
significance was observed for maternal age across all study groups (p = 0.065).
A significant decline in EGF levels were observed in PE compared to normotensive pregnancy,
regardless of HIV status (p = 0.0214). Based on HIV status, no statistical significance in EGF
concentration was observed (p = 0.6593).
EGFR was significantly elevated in normotensive pregnant compared to preeclamptic women (p
< 0.0001) (Figure 2A). In contrast, there were no significant differences of EGFR based on HIV
status alone (p = 0.2092) (Figure 2B). However, a significant up-regulation of EGFR was
observed between normotensive HIV positive compared to PE HIV positive women.
Normotensive HIV negative was also significantly up-regulated compared to PE HIV positive
(p < 0.0001). Normotensive HIV positive was significantly higher than PE HIV negative. Also,
of note within the PE group, HIV negative EGFR levels were significantly up-regulated
compared to the HIV positive group.
Conclusion: This novel study outlines a significant down-regulation of EGF and EGFR in PE
compared to normotensive pregnant women; regardless of HIV status. No significant
differences were observed based on HIV status alone for serum EGF levels. This could be due
to immune reconstruction as all HIV infected patients received HAART, hence may have
neutralised EGF levels. Furthermore, these findings may be attributed to the Trans-Activator of
transcription (Tat) protein which prevents EGF related function. However, for serum EGFR
concentration there were significant differences within PE group based on HIV status.
Significant differences were observed between normotensive and preeclamptic based on HIV
status, except for normotensive HIV negative vs PE HIV negative. Furthermore, there was no
significance in the normotensive group based on HIV status. The decreased levels of serum
EGF/ EGFR could possibly be used as a biomarker for PE development during pregnancy.
Isendlalelo: I-Epidermal growth factor iyiphrotheni okuthi uma ihlangene ne-epidermal growth
factor receptor, isiza ngokwandisa amaseli nokuwehlukanisa, yingakho ibalulekile
ekukhulelweni okujwayelekile okuphumelelayo. Ku-preeclampsia (PE), ukusayinda kwe-EGFR
kuyaphazamiseka okuholela ekwehleni kokugeleza kwegazi ku-fetus. Ngaphezu kwalokho,
ukusayina kwe-EGF / EGFR ngendlela eyehlukile kunalena eyejwayelekile kuholela
ekushodeni kwe-trophoblast. I-Trans-Activator of transcription (Tat) protein ivimbela izinqubo
ezihlobene ne-EGF uma ihlangene neHIV. Njengoba izifo ze-PE kanye ne-HIV kuyizimbangela
ezihamba phambili zokugula nokufa komama eNingizimu Afrika; lolu cwaningo lugxile
ekuhloleni ukusayina kwe-EGF / EGF-R ku-PE ehlobene ne-HIV kanye nomphumela wazo
uma zixhuma endaweni eziyihlosile maphansi neseli.
Izindlela: Ngemva kokugunyazwa kokuziphatha; lolu cwaningo lukhethe abesifazane
abakhulelwe abangama-80 kungobo yomlando yamasampula e-serum agcinwe ngokudlule.
Amasampula ahlukaniswa ngohlobo lokukhulelwa kanye nesimo se-HIV emaqenjini
alandelayo: a) abesifazane abakhulelwe abangenayo i-HIV kodwa abanomfutho wegazi
ophakeme (n=20), b) abesifazane abakhulelwe abane-HIV nomfutho wegazi ophakeme (n=20),
c) abesifazane abakhulelwe abangenayo i-HIV futhi abanomfutho wegazi ojwayelekile (n=20),
kanye d) nabesifazane abakhulelwe abane-HIV kodwa banomfutho wegazi ojwayelekile
(n=20). Kokubili i-EGF ne-EGF-R zacwaningwa ngendlela ye-Bioplex immunoassay ukuze
kutholwe inani lweserum yazo kuwo wonke amaqembu ocwaningo ngesikhathi.
Imiphumela: Ngokubuka idatha esungulwe yimtholampilo, umehluko obalulekile
ngokwezibalo watholwa kuwo wonke amaqembu eminyaka yobudala (p <0.001), isisindo
sokuzalwa (p <0.001), i-systolic BP (p <0.001), BMI (p = 0.048), i-diastolic BP (p <0.001)
kanye nesisindo sikamama (p = 0.002). Kodwa-ke awukho umehluko omkhulu ngokwezibalo
owabonwa ngeminyaka yobudala bomama kuwo wonke amaqembu ocwaningo (p = 0.065).
Ukwehla ngokwezibalo okubalulekile kwe-EGF kwabonwa i-PE uma kuqhathaniswa
nokukhulelwa kwe-normotensive, kungakhathaliseki isimo se-HIV (p = 0.0214). Ngokubuka
isimo se-HIV, akukho ukubaluleka kwezibalo kwe-EGF okuphawulwe (p = 0.6593).
Kungakhathalekile ukuthi ngabe i-HIV ithini, i-EGFR iphakanyiswe kakhulu kumanormotensive
abakhulelwe ngokuqhathaniswa nabesifazanebe-preeclamptic (p < 0.0001).
Ngokuphambene, kwakungekho umehluko ophawulekayo we-EGFR ngokusekelwe esimweni
se-HIV (p = 0.2092). Kodwa-ke, ukulawulwa okubalulekile kwe-EGFR kwabonwa phakathi
kwe-HIV positive normotensive uma kuqhathaniswa nabesifazane abakhulelwe abangenayo ixvi
HIV (p = 0.001); ngaleyo nkathi ukwehla okubalulekile kwe-EGFR kwaboniswe kuwo wonke
amaqembu ocwaningo (p = 0.001).
Isiphetho: Lolu cwaningo lwenoveli luveza ukwehla okubalulekile kwe-EGF ne-EGFR ku-PE
uma kuqhathaniswa nabesifazane abakhulelwe abajwayelekile; kungakhathaliseki isimo se-HIV.
Awukho mehluko omkhulu obonwe ngokusekelwe esimweni se-HIV. Lokhu kungase kube
ngenxa yokwakhiwa kabusha kwamasosha omzimba njengoba zonke iziguli ezine-HIV zithole
i-HAART, yingakho kungase kulinganise amazinga e-EGF/EGFR. Ngaphezu kwalokho, lokhu
okutholakele kungase kubalulwe ku-Trans-Activator of transcription (Tat) protein evimbela
umsebenzi ohlobene ne-EGF. I-down-regulation ye-EGF/EGFR ingase isetshenziswe
njengokuhlola inkomba yokubikezela ukuthuthukiswa kwe-PE ngesikhathi sokukhulelwa.
Description
Masters Degree. University of KwaZulu-Natal, Durban.