Open Access

miR‑320a upregulation contributes to the development of preeclampsia by inhibiting the growth and invasion of trophoblast cells by targeting interleukin 4

  • Authors:
    • Ning Xie
    • Zhi Jia
    • Li Li
  • View Affiliations

  • Published online on: August 8, 2019     https://doi.org/10.3892/mmr.2019.10574
  • Pages: 3256-3264
  • Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Preeclampsia (PE) is a serious pregnancy‑specific pathologic complication, and represents a primary cause of mother and fetus mortality. Abnormally expressed microRNAs (miRNAs) serve important regulatory roles in the development of PE. At present, the pathogenesis and molecular mechanism of PE remain unclear. The aim of the present study was to investigate the potential functions of miRNA (miR)‑320a in the human extravillous trophoblast cell line HTR‑8/SVneo and to identify the molecular mechanisms underlying miR‑320a function. Reverse transcription‑quantitative PCR was used in the present study to detect the levels of miR‑320a in the placentas of 57 pregnant patients with PE and 57 healthy pregnant patients. The effects of miR‑320a overexpression on the proliferation and invasion of HTR‑8/SVneo cells were determined using MTT and Transwell invasion assays. Western blot analysis and dual luciferase reporter assay were used to identify the genes targeted by miR‑320a. The present results suggested that miR‑320a expression level was decreased in placentas of patients with PE and the expression level of miR‑320a was found to be associated with the pathogenesis of PE (P<0.05). Overexpression of miR‑320a using miR‑320a mimics significantly inhibited cell proliferation and invasion in HTR‑8/SVneo cells in vitro (P<0.05). Furthermore, interleukin (IL)‑4 was identified to be a direct target gene of miR‑320a. miR‑320a could repress IL‑4 expression by binding to its 3' untranslated region (P<0.05). Mechanistic studies suggested that IL‑4 was a functional target gene of miR‑320a, and miR‑320a upregulation inhibited the proliferation and invasion of HTR‑8/SVneo cells by directly targeting IL‑4 (P<0.05). Collectively, to the best of our knowledge, the present study is the first to suggest that miR‑320a may be a downregulated miRNA during PE, and IL‑4 may act as a functional target gene of miR‑320a. The present study suggested that miR‑320a upregulation was involved in the development of PE by inhibiting the proliferation and invasion of trophoblast cells by targeting IL‑4, indicating that the miR‑320a/IL‑4 pathway may represent a novel therapeutic target for PE treatment.

References

1 

Redman CW and Sargent IL: Latest advances in understanding preeclampsia. Science. 308:1592–1594. 2005. View Article : Google Scholar : PubMed/NCBI

2 

Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM and Hofmeyr GJ: Pre-eclampsia. Lancet. 387:999–1011. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Amaral LM, Wallace K, Owens M and LaMarca B: Pathophysiology and current clinical management of preeclampsia. Curr Hypertens Rep. 19:612017. View Article : Google Scholar : PubMed/NCBI

4 

Ji L, Brkic J, Liu M, Fu G, Peng C and Wang YL: Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med. 34:981–1023. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Staun-Ram E and Shalev E: Human trophoblast function during the implantation process. Reprod Biol Endocrinol. 3:562005. View Article : Google Scholar : PubMed/NCBI

6 

Noris M, Perico N and Remuzzi G: Mechanisms of disease: Pre-eclampsia. Nat Clin Pract Nephrol. 1:98–114; quiz 120. 2005. View Article : Google Scholar : PubMed/NCBI

7 

He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Schickel R, Boyerinas B, Park SM and Peter ME: MicroRNAs: Key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 27:5959–5974. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Shenouda SK and Alahari SK: MicroRNA function in cancer: Oncogene or a tumor suppressor? Cancer Metastasis Rev. 28:369–378. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Chen DB and Wang W: Human placental microRNAs and preeclampsia. Biol Reprod. 88:1302013. View Article : Google Scholar : PubMed/NCBI

12 

Xiao J, Tao T, Yin Y, Zhao L, Yang L and Hu L: miR-144 may regulate the proliferation, migration and invasion of trophoblastic cells through targeting PTEN in preeclampsia. Biomed Pharmacother. 94:341–353. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Wu L, Song WY, Xie Y, Hu LL, Hou XM, Wang R, Gao Y, Zhang JN, Zhang L, Li WW, et al: miR-181a-5p suppresses invasion and migration of HTR-8/SVneo cells by directly targeting IGF2BP2. Cell Death Dis. 9:162018. View Article : Google Scholar : PubMed/NCBI

14 

Dai Y, Qiu Z, Diao Z, Shen L, Xue P, Sun H and Hu Y: MicroRNA-155 inhibits proliferation and migration of human extravillous trophoblast derived HTR-8/SVneo cells via down-regulating cyclin D1. Placenta. 33:824–829. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Liu F, Wu K, Wu W, Chen Y, Wu H, Wang H and Zhang W: miR203 contributes to preeclampsia via inhibition of VEGFA expression. Mol Med Rep. 17:5627–5634. 2018.PubMed/NCBI

16 

Sun L, Liu B, Lin Z, Yao Y, Chen Y, Li Y, Chen J, Yu D, Tang Z, Wang B, et al: miR-320a acts as a prognostic factor and inhibits metastasis of salivary adenoid cystic carcinoma by targeting ITGB3. Mol Cancer. 14:962015. View Article : Google Scholar : PubMed/NCBI

17 

Li Y, Liu H, Shao J and Xing G: miR-320a serves as a negative regulator in the progression of gastric cancer by targeting RAB14. Mol Med Rep. 16:2652–2658. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Wang J, Shi C, Cao L, Zhong L and Wang D: MicroRNA-320a is downregulated in non-small cell lung cancer and suppresses tumor cell growth and invasion by directly targeting insulin-like growth factor 1 receptor. Oncol Lett. 13:3247–3252. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Lv G, Wu M, Wang M, Jiang X, Du J, Zhang K, Li D, Ma N, Peng Y, Wang L, et al: miR-320a regulates high mobility group box 1 expression and inhibits invasion and metastasis in hepatocellular carcinoma. Liver Int. 37:1354–1364. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Zhao H, Dong T, Zhou H, Wang L, Huang A, Feng B, Quan Y, Jin R, Zhang W, Sun J, et al: miR-320a suppresses colorectal cancer progression by targeting Rac1. Carcinogenesis. 35:886–895. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

22 

Agarwal V, Bell GW, Nam JW and Bartel DP: Predicting effective microRNA target sites in mammalian mRNAs. Elife. 4:2015. View Article : Google Scholar

23 

Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M and Rajewsky N: Combinatorial microRNA target predictions. Nat Genet. 37:495–500. 2005. View Article : Google Scholar : PubMed/NCBI

24 

John B, Enright AJ, Aravin A, Tuschl T, Sander C and Marks DS: Human MicroRNA targets. PLoS Biol. 2:e3632004. View Article : Google Scholar : PubMed/NCBI

25 

Chen J, Zhong M and Yu YH: Association between interleukin-4 polymorphisms and risk of pre-eclampsia in a population of Chinese pregnant women. Genet Mol Res. 16:2017. View Article : Google Scholar

26 

Zhang Z, Wang X, Zhang L, Shi Y, Wang J and Yan H: Wnt/β-catenin signaling pathway in trophoblasts and abnormal activation in preeclampsia (Review). Mol Med Rep. 16:1007–1013. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Pineles BL, Romero R, Montenegro D, Tarca AL, Han YM, Kim YM, Draghici S, Espinoza J, Kusanovic JP, Mittal P, et al: Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J Obstet Gynecol. 196:261, e1–e6. 2007. View Article : Google Scholar

28 

Zhu XM, Han T, Sargent IL, Yin GW and Yao YQ: Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs. normal pregnancies. Am J Obstet Gynecol. 200:661, e1–e7. 2009. View Article : Google Scholar

29 

Jairajpuri DS and Almawi WY: MicroRNA expression pattern in pre-eclampsia (Review). Mol Med Rep. 13:2351–2358. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Noguer-Dance M, Abu-Amero S, Al-Khtib M, Lefèvre A, Coullin P, Moore GE and Cavaillé J: The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum Mol Genet. 19:3566–3582. 2010. View Article : Google Scholar : PubMed/NCBI

31 

Lu C, Liao Z, Cai M and Zhang G: MicroRNA-320a downregulation mediates human liver cancer cell proliferation through the Wnt/beta-catenin signaling pathway. Oncol Lett. 13:573–578. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Zhang Y, He X, Liu Y, Ye Y, Zhang H, He P, Zhang Q, Dong L, Liu Y and Dong J: microRNA-320a inhibits tumor invasion by targeting neuropilin 1 and is associated with liver metastasis in colorectal cancer. Oncol Rep. 27:685–694. 2012.PubMed/NCBI

33 

Xie F, Yuan Y, Xie L, Ran P, Xiang X, Huang Q, Qi G, Guo X, Xiao C and Zheng S: miRNA-320a inhibits tumor proliferation and invasion by targeting c-Myc in human hepatocellular carcinoma. Onco Targets Ther. 10:885–894. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Li H, Yu L, Liu J, Bian X, Shi C, Sun C, Zhou X, Wen Y, Hua D, Zhao S, et al: miR-320a functions as a suppressor for gliomas by targeting SND1 and beta-catenin, and predicts the prognosis of patients. Oncotarget. 8:19723–19737. 2017.PubMed/NCBI

35 

Singh VK and Rai G: Cytokines in posterior uveitis: An update. Immunol Res. 23:59–74. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Kang L, Chen CH, Yu CH, Chang CH and Chang FM: An association study of interleukin-4 gene and preeclampsia in Taiwan. Taiwan J Obstet Gynecol. 53:215–219. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Hashemi V, Dolati S, Hosseini A, Gharibi T, Danaii S and Yousefi M: Natural killer T cells in Preeclampsia: An updated review. Biomed Pharmacother. 95:412–418. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Vianna P, Mondadori AG, Bauer ME, Dornfeld D and Chies JA: HLA-G and CD8+ regulatory T cells in the inflammatory environment of pre-eclampsia. Reproduction. 152:741–751. 2016. View Article : Google Scholar : PubMed/NCBI

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October 2019
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APA
Xie, N., Jia, Z., & Li, L. (2019). miR‑320a upregulation contributes to the development of preeclampsia by inhibiting the growth and invasion of trophoblast cells by targeting interleukin 4. Molecular Medicine Reports, 20, 3256-3264. https://doi.org/10.3892/mmr.2019.10574
MLA
Xie, N., Jia, Z., Li, L."miR‑320a upregulation contributes to the development of preeclampsia by inhibiting the growth and invasion of trophoblast cells by targeting interleukin 4". Molecular Medicine Reports 20.4 (2019): 3256-3264.
Chicago
Xie, N., Jia, Z., Li, L."miR‑320a upregulation contributes to the development of preeclampsia by inhibiting the growth and invasion of trophoblast cells by targeting interleukin 4". Molecular Medicine Reports 20, no. 4 (2019): 3256-3264. https://doi.org/10.3892/mmr.2019.10574