MiR-30a-3p Targeting FLT1 Modulates Trophoblast Cell Proliferation in the Pathogenesis of Preeclampsia

Abstract

Preeclampsia (PE) may pose significant adverse effects on pregnant women. Dysregulation of angiogenesis, trophoblast invasion, and proliferation are known to be associated with PE development and progression. Fms related tyrosine kinase 1 (FLT1), an anti-angiogenic factor, is consistently upregulated in PE patients. Recent papers highlight that aberrant miR-30a-3p expression contributes to PE development. More effects are needed to assess the biological function of placental miR-30a-3p in PE. The soluble FLT1 (sFLT1) and FLT1 levels were tested by ELISA assay and Western blotting assay. mRNA levels were measured by RT-qPCR assay. Colony formation and MTT assays were applied to assess the effect of miR-30a-3p on trophoblast cell proliferation. The serum sFLT1 and placental FLT1 levels were substantially high in patients with PE. Using miRNA microarray assay, we identified miR-30a-3p upregulation in PE patients’ placenta tissues. We further confirmed that miR-30a-3p binds to the 3′-UTR of FLT1 gene and positively regulate its expression. Forcing miR-30a-3p expression inhibited trophoblast cell proliferation and vice versa. In conclusion, persistent high levels of FLT1 and miR-30a-3p may pose adverse effects on angiogenesis and trophoblast proliferation in placenta of PE patients. Therefore, targeting FLT1 and miR-30a-3p may serve as ideal strategies for managing patients with PE.

Key words

cell - steroid hormones - fertility

• References

• 1 Gathiram P, Moodley J. Pre-eclampsia: its pathogenesis and pathophysiolgy. Cardiovasc J Afr 2016; 27: 71-78
• 2 Uzan J, Carbonnel M, Piconne O. et al. Pre-eclampsia: pathophysiology, diagnosis, and management. Vasc Health Risk Manag 2011; 7: 467-474
• 3 Gude NM, Roberts CT, Kalionis B. et al. Growth and function of the normal human placenta. Thromb Res 2004; 114: 397-407
• 4 Huang J, Zheng L, Kong H. et al. miR-139-5p promotes the proliferation and invasion of trophoblast cells by targeting sFlt-1 in preeclampsia. Placenta 2020; 92: 37-43
• 5 Qi T, Zhang D, Shi X. et al. Decreased circUBAP2 expression is associated with preeclampsia by limiting trophoblast cell proliferation and migration. Reprod Sci 2021; 28: 2237-2245
• 6 Robertson SA. Preventing preeclampsia by silencing soluble Flt-1?. N Engl J Med 2019; 380: 1080-1082
• 7 Woolcock J, Hennessy A, Xu B. et al. Soluble Flt-1 as a diagnostic marker of pre-eclampsia. Aust N Z J Obstet Gynaecol 2008; 48: 64-70
• 8 Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013; 12: 847-865
• 9 Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci 2016; 17: 1712
• 10 Shukla GC, Singh J, Barik S. MicroRNAs: Processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 2011; 3: 83-92
• 11 Tufekci KU, Oner MG, Meuwissen RL. et al. The role of microRNAs in human diseases. Methods Mol Biol 2014; 1107: 33-50
• 12 Paul P, Chakraborty A, Sarkar D. et al. Interplay between miRNAs and human diseases. J Cell Physiol 2018; 233: 2007-2018
• 13 Lv Y, Lu C, Ji X. et al. Roles of microRNAs in preeclampsia. J Cell Physiol 2019; 234: 1052-1061
• 14 Choi SY, Yun J, Lee OJ. et al. MicroRNA expression profiles in placenta with severe preeclampsia using a PNA-based microarray. Placenta 2013; 34: 799-804
• 15 Lykoudi A, Kolialexi A, Lambrou GI. et al. Dysregulated placental microRNAs in early and late onset preeclampsia. Placenta 2018; 61: 24-32
• 16 Niu ZR, Han T, Sun XL. et al. MicroRNA-30a-3p is overexpressed in the placentas of patients with preeclampsia and affects trophoblast invasion and apoptosis by its effects on IGF-1. Am J Obstet Gynecol 2018; 218: 249 e241-249 e212
• 17 Zhang H, He Y, Wang JX. et al. miR-30-5p-mediated ferroptosis of trophoblasts is implicated in the pathogenesis of preeclampsia. Redox Biol 2020; 29: 101402
• 18 Hod T, Cerdeira AS, Karumanchi SA. Molecular mechanisms of preeclampsia. Cold Spring Harb Perspect Med 2015; 5: a023473
• 19 McGinnis R, Steinthorsdottir V, Williams NO. et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat Genet 2017; 49: 1255-1260
• 20 Maynard SE, Min JY, Merchan J. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649-658
• 21 Wang W, Feng L, Zhang H. et al. Preeclampsia up-regulates angiogenesis-associated microRNA (i. e., miR-17, -20a, and -20b) that target ephrin-B2 and EPHB4 in human placenta. J Clin Endocrinol Metab 2012; 97: E1051-E1059
• 22 Zhou C, Zou QY, Li H. et al. Preeclampsia downregulates microRNAs in fetal endothelial cells: roles of miR-29a/c-3p in endothelial function. J Clin Endocrinol Metab 2017; 102: 3470-3479
• 23 Chelbi ST, Wilson ML, Veillard AC. et al. Genetic and epigenetic mechanisms collaborate to control SERPINA3 expression and its association with placental diseases. Hum Mol Genet 2012; 21: 1968-1978
• 24 Zhou F, Sun Y, Gao Q. et al. microRNA-21 regulates the proliferation of placental cells via FOXM1 in preeclampsia. Exp Ther Med 2020; 20: 1871-1878
• 25 Bounds KR, Chiasson VL, Pan LJ. et al. MicroRNAs: new players in the pathobiology of preeclampsia. Front Cardiovasc Med 2017; 4: 60
• 26 Liu M, Roth A, Yu M. et al. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes Dev 2013; 27: 2543-2548
• 27 Zhang Y, Fan M, Geng G. et al. A novel HIV-1-encoded microRNA enhances its viral replication by targeting the TATA box region. Retrovirology 2014; 11: 23