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Human umbilical cord blood mesenchymal stem cells-derived exosomal microRNA-503-3p inhibits progression of human endometrial cancer cells through downregulating MEST



Endometrial cancer (EC) is a group of epithelial malignant tumors that occur in the endometrium. The specific pathogenesis is not revealed, hence, the goal of this study was to investigate the influence of human umbilical cord blood mesenchymal stem cells (hUMSCs)-derived exosomal microRNA-503-3p (miR-503-3p) on human EC cells by mediating mesoderm-specific transcript (MEST). The binding relationship between MiR-503-3p and MEST was searched. HUMSCs were collected and exosomes (Exos) were isolated and identified. Human EC cell lines HEC-1B and RL95-2 were transfected with elevated miR-503-3p or silenced MEST vector or co-cultured with Exos to figure their roles in biological functions of EC cells. The in vitro effect of miR-503-3p, MEST, and Exos on EC cells was further verified in vivo. MEST was a target of miR-503-3p. Overexpression of miR-503-3p or reduction of MEST suppressed the biological functions of EC cells. Enhanced MEST expression mitigated the role of upregulated miR-503-3p on the growth of EC cells. HUMSCs-derived Exos suppressed EC cell growth, upregulated miR-503-3p-modified HUMSCs-derived Exos had a more obvious inhibitory effect on EC cell growth. The anti-tumor effect of elevated miR-503-3p, silenced MEST, and HUMSCs-derived Exos were verified in nude mice. This study highlights that hUMSCs-derived exosomal miR-503-3p inhibits EC development by suppressing MEST, which is of great benefit to EC therapy.

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Fig. 1: miR-503-3p is poorly expressed and targets MEST in EC cells.
Fig. 2: Overexpression of miR-503-3p or reduction of MEST inhibits the progression of HEC-1B cells.
Fig. 3: Upregulating MEST reverses the inhibitory effect of miR-503-3p on HEC-1B cells.
Fig. 4: Identification of hUMSCs.
Fig. 5: Identification of hUMSCs-derived Exos.
Fig. 6: HUMSCs-derived Exos containing miR-503-3p repress the progression of HEC-1B cells.
Fig. 7: Overexpressed exosomal miR-503-3p decreases tumor weight and volume of EC in vivo.


  1. Zhang G, Ma A, Jin Y, Pan G, Wang C. LncRNA SNHG16 induced by TFAP2A modulates glycolysis and proliferation of endometrial carcinoma through miR-490-3p/HK2 axis. Am J Transl Res. 2019;11:7137–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu MC, Gardner AB, Wolford JE, Tewari KS. Endometrial cancer in the morbidly obese: a review. Curr Opin Obstet Gynecol. 2020;32:42–50.

    Article  Google Scholar 

  3. Zhang Y, Zhang P, Chen L, Zhao L, Zhu J, Zhu T. The long non-coding RNA-14327.1 promotes migration and invasion potential of endometrial carcinoma cells by stabilizing the Potassium channel Kca3.1. Onco Targets Ther. 2019;12:10287–97.

    Article  CAS  Google Scholar 

  4. Xiao YY, Lin L, Li YH, Jiang HP, Zhu LT, Deng YR, et al. ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription. Am J Cancer Res. 2019;9:2314–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu Y, Chi S, Zhou X, Zhao R, Xiao C, Wang H. Prognostic value of distant metastatic sites in stage IV endometrial cancer: a SEER database study of 2948 women. Int J Gynaecol Obstet. 2019;149:16–23.

    Article  Google Scholar 

  6. Bateman NW, Teng PN, Hope E, Hood BL, Oliver J, W Ao W, et al. Jupiter microtubule-associated homolog 1 (JPT1): a predictive and pharmacodynamic biomarker of metformin response in endometrial cancers. Cancer Med. 2019;9:1092–103.

    Article  Google Scholar 

  7. Shi F, Wang T, Liu Z, Zhang Y, Wang J, Zhang K, et al. LncRNA miR143HG up-regulates p53 in endometrial carcinoma by sponging miR-125a. Cancer Manag Res. 2019;11:10117–23.

    Article  CAS  Google Scholar 

  8. Wang Z, Dong S, Chen Q, Chen C, Xu Z, Dong Z. Analysis of the MicroRNA profile by sequencing in ovarian granular cells from women suffering fluorosis with reproductive dysfunction. Biol Trace Elem Res. 2019;197:101–106.

    Article  Google Scholar 

  9. Devor EJ, Cha E, Warrier A, Miller MD, Gonzalez-Bosquet J, Leslie KK. The miR-503 cluster is coordinately under-expressed in endometrial endometrioid adenocarcinoma and targets many oncogenes, cell cycle genes, DNA repair genes and chemotherapy response genes. Onco Targets Ther. 2018;11:7205–11.

    Article  CAS  Google Scholar 

  10. Xu YY, Wu HJ, Ma HD, Xu LP, Huo Y, Yin LR. MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1. FEBS J. 2013;280:3768–79.

    Article  CAS  Google Scholar 

  11. Wang X, Wan L, Weng X, Xie J, Zhang A, Liu Y, et al. Alteration in methylation level at differential methylated regions of MEST and DLK1 in fetus of preeclampsia. Hypertens Pregnancy. 2018;37:1–8.

    Article  Google Scholar 

  12. Minchenko OH, Tsymbal DO, Minchenko DO, Kubaychuk OO. Hypoxic regulation of MYBL1, MEST, TCF3, TCF8, GTF2B, GTF2F2 and SNAI2 genes expression in U87 glioma cells upon IRE1 inhibition. Ukr Biochem J. 2016;88:52–62.

    Article  CAS  Google Scholar 

  13. Vidal AC, Henry NM, Murphy SK, Oneko O, Nye M, Bartlett JA, et al. PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer. Clin Transl Oncol. 2014;16:266–72.

    Article  CAS  Google Scholar 

  14. Seo M, Kim SM, Woo EY, Han KC, Park EJ, Ko S, et al. Stemness-attenuating miR-503-3p as a paracrine factor to regulate growth of cancer stem cells. Stem Cells Int. 2018;2018:4851949.

    PubMed  PubMed Central  Google Scholar 

  15. Chen W, Zheng P, Hong T, Wang Y, Liu N, He B, et al. Astrocytes-derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1-20 k. J Tissue Eng Regen Med. 2019;14:412–23.

    Article  Google Scholar 

  16. Srivastava A, Moxley K, Ruskin R, Dhanasekaran DN, Zhao YD, Ramesh R. A non-invasive liquid biopsy screening of urine-derived exosomes for miRNAs as biomarkers in endometrial cancer patients. AAPS J. 2018;20:82.

    Article  Google Scholar 

  17. Ayuk SM, Abrahamse H, Houreld NN. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro. J Photochem Photobio B. 2016;161:368–74.

    Article  CAS  Google Scholar 

  18. Fu YS, Cheng YC, Lin MY, Cheng H, Chu PM, Chou SC, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells. 2006;24:115–24.

    Article  Google Scholar 

  19. Hang H, Yu Y, Wu N, Huang Q, Xia Q, Bian J. Induction of highly functional hepatocytes from human umbilical cord mesenchymal stem cells by HNF4alpha transduction. PLoS One. 2014;9:e104133.

    Article  Google Scholar 

  20. Zhang J, Chen C, Hu B, Niu X, Liu X, Zhang G, et al. Exosomes derived from human endothelial progenitor cells accelerate cutaneous wound healing by promoting angiogenesis through Erk1/2 signaling. Int J Biol Sci. 2016;12:1472–87.

    Article  CAS  Google Scholar 

  21. Wang ZF, Liao F, Wu H, Dai J. Glioma stem cells-derived exosomal miR-26a promotes angiogenesis of microvessel endothelial cells in glioma. J Exp Clin Cancer Res. 2019;38:201.

    Article  Google Scholar 

  22. Sun Y, Li L, Xing S, Pan Y, Shi Y, Zhang L, et al. miR-503-3p induces apoptosis of lung cancer cells by regulating p21 and CDK4 expression. Cancer Biomark. 2017;20:597–608.

    Article  CAS  Google Scholar 

  23. Zhu X, Su D, Xuan S, Ma G, Dai Z, Liu T, et al. Gene therapy of gastric cancer using LIGHT-secreting human umbilical cord blood-derived mesenchymal stem cells. Gastric Cancer. 2013;16:155–66.

    Article  CAS  Google Scholar 

  24. Gondi CS, Veeravalli KK, Gorantla B, Dinh DH, Fassett D, Klopfenstein JD, et al. Human umbilical cord blood stem cells show PDGF-D-dependent glioma cell tropism in vitro and in vivo. Neuro Oncol. 2010;12:453–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ma Y, Hao X, Zhang S, Zhang J. The in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cells. Breast Cancer Res Treat. 2012;133:473–85.

    Article  CAS  Google Scholar 

  26. Kooijmans SAA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJA, et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172:229–38.

    Article  CAS  Google Scholar 

  27. Zhu C, Ding H, Yang J, Zhou Y, Luo Y, Shi S, et al. Downregulation of proline hydroxylase 2 and upregulation of hypoxia-inducible factor 1alpha are associated with endometrial cancer aggressiveness. Cancer Manag Res. 2019;11:9907–12.

    Article  CAS  Google Scholar 

  28. Moon YS, Park SK, Kim HT, Lee TS, Kim JH, Choi YS. Imprinting and expression status of isoforms 1 and 2 of PEG1/MEST gene in uterine leiomyoma. Gynecol Obstet Invest. 2010;70:120–5.

    Article  CAS  Google Scholar 

  29. Li W, Li J, Mu H, Guo M, Deng H. MiR-503 suppresses cell proliferation and invasion of gastric cancer by targeting HMGA2 and inactivating WNT signaling pathway. Cancer Cell Int. 2019;19:164.

    Article  Google Scholar 

  30. Kim MS, Lee HS, Kim YJ, Lee DY, Kang SG, Jin W. MEST induces Twist-1-mediated EMT through STAT3 activation in breast cancers. Cell Death Differ. 2019;26:2594–606.

    Article  CAS  Google Scholar 

  31. Boot A, Oosting J, de Miranda NF, Zhang Y, Corver WE, van de Water B, et al. Imprinted survival genes preclude loss of heterozygosity of chromosome 7 in cancer cells. J Pathol. 2016;240:72–83.

    Article  CAS  Google Scholar 

  32. Lian Z, Hu Z, Xian H, Jiang R, Huang H, Jiang Y, et al. Exosomes derived from normal human bronchial epithelial cells down-regulate proliferation and migration of hydroquinone-transformed malignant recipient cells via up-regulating PTEN expression. Chemosphere. 2019;244:125496.

    Article  Google Scholar 

  33. Li H, Chi X, Li R, Ouyang J, Chen Y. HIV-1-infected cell-derived exosomes promote the growth and progression of cervical cancer. Int J Biol Sci. 2019;15:2438–47.

    Article  CAS  Google Scholar 

  34. Yu X, Zhang Q, Zhang X, Han Q, Li H, Mao Y, et al. Exosomes from macrophages exposed to apoptotic breast cancer cells promote breast cancer proliferation and metastasis. J Cancer. 2019;10:2892–906.

    Article  CAS  Google Scholar 

  35. Li BL, Lu W, Qu JJ, Ye L, Du GQ, Wan XP. Loss of exosomal miR-148b from cancer-associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis. J Cell Physiol. 2019;234:2943–53.

    Article  CAS  Google Scholar 

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This study was supported by Research on Key Technologies of Adipose Mesenchymal Stem Cells in the Treatment of Premature Ovarian Failure Related Diseases. (No. 20200708082YY).

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HZ finished study design; YJ and ZQ finished experimental studies; Yiang and Jing Jiang finished data analysis, and Ying Jiang finished manuscript editing. All authors read and approved the final manuscript.

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Correspondence to Hong Zhang.

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Pan, Y., Wang, X., Li, Y. et al. Human umbilical cord blood mesenchymal stem cells-derived exosomal microRNA-503-3p inhibits progression of human endometrial cancer cells through downregulating MEST. Cancer Gene Ther 29, 1130–1139 (2022).

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