Advertisement

LncRNA XIST inhibits ovarian cancer cell growth and metastasis via regulating miR-150-5p/PDCD4 signaling pathway

  • Shuli Wang
  • Guanzhen LiEmail author
Original Article
  • 27 Downloads

Abstract

The aim of this study was to explore the role of X-inactive specific transcript (XIST), miR-150-5p, and programmed cell death protein 4 (PDCD4) in the pathogenesis of ovarian cancer (OC). The expression levels of XIST, miR-150-5p, and PDCD4 were examined by qRT-PCR or Western blotting as appropriate. The proliferation, apoptosis, migration, and invasiveness of human OC cell lines in vitro were respectively evaluated by CCK-8, TUNEL, wound-healing assay, and transwell assay. A xenograft model of OC was also established to determine the effect of XIST knockdown on tumor growth in vivo. Finally, direct binding between XIST and miR-150-5p and between miR-150-5p and PDCD4 were verified by dual-luciferase reported assay. XIST was significantly downregulated in OC tissues and cell lines compared with the normal ovarian epithelial tissues and cells. XIST knockdown in OC cells significantly facilitated cell growth, migration, and invasion and inhibited apoptosis. In addition, silencing XIST also initiated epithelial-mesenchymal transition (EMT) and conferred cancer stem cell (CSC) survival in vitro. Consistent with the in vitro findings, knockdown of XIST promoted tumorigenesis, suppressed PDCD4, and upregulated miR-150-5p in vivo. XIST directly bound to and downregulated miR-150-5p in OC tissues and cell lines. Furthermore, PDCD4 was identified as the target gene of miR-150-5p, and XIST knockdown downregulated PDCD4 by relieving miR-150-5p inhibition. Finally, blocking miR-150-5p partly abolished the effects of XIST knockdown in vitro. Taken together, XIST inhibits OC growth and metastasis by upregulating PDCD4 via miR-150-5p suppression.

Keywords

XIST miR-150-5p PDCD4 Metastasis Ovarian cancer 

Notes

Author Contribution

Guanzhen Li designed the study, performed the experiments, and analyzed the data.

Shuli Wang performed the experiments, analyzed the data, and wrote the paper.

Compliance with ethical standards

The protocol for the current study was reviewed by the Clinical Research Ethics Committee of the Provincial Hospital Affiliated to Shandong University (No. 20180725), and written consent was obtained from all patients.

References

  1. Brungs D, Lochhead A, Iyer A et al (2019) Expression of cancer stem cell markers is prognostic in metastatic gastroesophageal adenocarcinoma. PathologyGoogle Scholar
  2. Chen Z, Hu X, Wu Y, Cong L, He X, Lu J, Feng J, Liu D (2019) Long non-coding RNA XIST promotes the development of esophageal cancer by sponging miR-494 to regulate CDK6 expression. Biomed Pharmacother 109:2228–2236PubMedCrossRefGoogle Scholar
  3. Clarke MF (2019) Clinical and therapeutic implications of cancer stem cells. N Engl J Med 380(23):2237–2245PubMedCrossRefGoogle Scholar
  4. Coburn SB, Bray F, Sherman ME et al (2017) International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. Int J Cancer 140(11):2451–2460PubMedPubMedCentralCrossRefGoogle Scholar
  5. Du Y, Weng XD, Wang L et al (2017) LncRNA XIST acts as a tumor suppressor in prostate cancer through sponging miR-23a to modulate RKIP expression. Oncotarget 8(55):94358–94370PubMedPubMedCentralCrossRefGoogle Scholar
  6. Han M, Gao H, Ju P, Gao MQ, Yuan YP, Chen XH, Liu KL, Han YT, Han ZW (2018) Hispidulin inhibits hepatocellular carcinoma growth and metastasis through AMPK and ERK signaling mediated activation of PPARgamma. Biomed Pharmacother 103:272–283PubMedCrossRefGoogle Scholar
  7. Han M, Gao H, Xie J, Yuan YP, Yuan Q, Gao MQ, Liu KL, Chen XH, Han YT, Han ZW (2019) Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway. Acta Pharmacol Sin 40(5):666–676PubMedCrossRefGoogle Scholar
  8. Hardin H, Zhang R, Helein H, Buehler D, Guo Z, Lloyd RV (2017) The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors. Lab Investig 97(10):1142–1151PubMedCrossRefGoogle Scholar
  9. Hu X, Wang Y, Liang H et al (2017) miR-23a/b promote tumor growth and suppress apoptosis by targeting PDCD4 in gastric cancer. Cell Death Dis 8(10):e3059PubMedPubMedCentralCrossRefGoogle Scholar
  10. Hu X, Liu Y, Du Y et al (2019) Long non-coding RNA BLACAT1 promotes breast cancer cell proliferation and metastasis by miR-150-5p/CCR2. Cell Biosci 9:14PubMedPubMedCentralCrossRefGoogle Scholar
  11. Huang YS, Chang CC, Lee SS et al (2016) Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression. Oncotarget 7(28):43256–43266PubMedPubMedCentralGoogle Scholar
  12. Jin H, Jin X, Chai W, Yin Z, Li Y, Dong F, Wang W (2019) Long non-coding RNA MIAT competitively binds miR-150-5p to regulate ZEB1 expression in osteosarcoma. Oncol Lett 17(1):1229–1236PubMedGoogle Scholar
  13. Kawasaki H, Taira K (2003) Hes1 is a target of microRNA-23 during retinoic-acid-induced neuronal differentiation of NT2 cells. Nature 423(6942):838–842PubMedCrossRefGoogle Scholar
  14. Krell J, Stebbing J, Carissimi C, Dabrowska AF, de Giorgio A, Frampton AE, Harding V, Fulci V, Macino G, Colombo T, Castellano L (2016) TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network. Genome Res 26(3):331–341PubMedPubMedCentralCrossRefGoogle Scholar
  15. Lawson J, Dickman C, MacLellan S, Towle R, Jabalee J, Lam S, Garnis C (2017) Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells. Oncotarget 8(48):83913–83924PubMedPubMedCentralCrossRefGoogle Scholar
  16. Liu H, Deng H, Zhao Y et al (2018) LncRNA XIST/miR-34a axis modulates the cell proliferation and tumor growth of thyroid cancer through MET-PI3K-AKT signaling. J Exp Clin Cancer Res 37(1):279PubMedPubMedCentralCrossRefGoogle Scholar
  17. Liu A, Liu L, Lu H (2019) LncRNA XIST facilitates proliferation and epithelial-mesenchymal transition of colorectal cancer cells through targeting miR-486-5p and promoting neuropilin-2. J Cell Physiol 234(8):13747–13761PubMedCrossRefGoogle Scholar
  18. Ma J, Xuan SH, Li Y, Zhang ZP, Li XH (2017) Role of the TGFbeta/PDCD4/AP-1 signaling pathway in nasopharyngeal carcinoma and its relationship to prognosis. Cell Physiol Biochem 43(4):1392–1401PubMedCrossRefGoogle Scholar
  19. Medema JP (2013) Cancer stem cells: the challenges ahead. Nat Cell Biol 15(4):338–344PubMedCrossRefPubMedCentralGoogle Scholar
  20. Nan Y, Guo H, Guo L, Wang L, Ren B, Yu K, Huang Q, Zhong Y (2018) MiRNA-451 inhibits glioma cell proliferation and invasion through the mTOR/HIF-1alpha/VEGF signaling pathway by targeting CAB39. Hum Gene Ther Clin Dev 29(3):156–166PubMedCrossRefGoogle Scholar
  21. Overton HA, Ihara T, Bishop DH (1987) Identification of the N and NSS proteins coded by the ambisense S RNA of Punta Toro phlebovirus using monospecific antisera raised to baculovirus expressed N and NSS proteins. Virology 157(2):338–350PubMedCrossRefGoogle Scholar
  22. Pavan S, Meyer-Schaller N, Diepenbruck M et al (2018) A kinome-wide high-content siRNA screen identifies MEK5-ERK5 signaling as critical for breast cancer cell EMT and metastasis. Oncogene 37(31):4197–4213PubMedCrossRefGoogle Scholar
  23. Pradella D, Naro C, Sette C, Ghigna C (2017) EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer 16(1):8PubMedPubMedCentralCrossRefGoogle Scholar
  24. Shah S, Pocard M, Mirshahi M (2019) Targeting the differentiation of gastric cancer cells (KATOIII) downregulates epithelial mesenchymal and cancer stem cell markers. Oncol RepGoogle Scholar
  25. Srivastava C, Irshad K, Dikshit B et al (2018) FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma. Int J Cancer 142(4):805–812PubMedCrossRefGoogle Scholar
  26. Sun K, Jia Z, Duan R, Yan Z, Jin Z, Yan L, Li Q, Yang J (2019) Long non-coding RNA XIST regulates miR-106b-5p/P21 axis to suppress tumor progression in renal cell carcinoma. Biochem Biophys Res Commun 510(3):416–420PubMedCrossRefGoogle Scholar
  27. Suo T, Chen GZ, Huang Y et al (2018) miRNA-1246 suppresses acute lung injury-induced inflammation and apoptosis via the NF-kappaB and Wnt/beta-catenin signal pathways. Biomed Pharmacother 108:783–791PubMedCrossRefGoogle Scholar
  28. Tao L, Wu YQ, Zhang SP (2019) MiR-21-5p enhances the progression and paclitaxel resistance in drug-resistant breast cancer cell lines by targeting PDCD4. Neoplasma 2019Google Scholar
  29. Thin KZ, Liu X, Feng X et al (2018) LncRNA-DANCR: a valuable cancer related long non-coding RNA for human cancers. Pathol Res Pract 214(6):801–805PubMedCrossRefGoogle Scholar
  30. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68(4):284–296PubMedPubMedCentralCrossRefGoogle Scholar
  31. Vishwakarma SK, Lakkireddy C, Sravani G, Sastry BVS, Raju N, Ahmed SI, Khan AA, Owaisi N, Jaisawal A, Khan MA, Khan AA (2018) Association of CD14 and macrophage migration inhibitory factor gene polymorphisms with inflammatory microRNAs expression levels in ankylosing spondylitis and polyarthralgia. Int J Immunogenet 45(4):190–200PubMedCrossRefGoogle Scholar
  32. Wang Q, Yang HS (2018) The role of Pdcd4 in tumour suppression and protein translation. Biol CellGoogle Scholar
  33. Wang C, Qi S, Xie C, Li C, Wang P, Liu D (2018) Upregulation of long non-coding RNA XIST has anticancer effects on epithelial ovarian cancer cells through inverse downregulation of hsa-miR-214-3p. J Gynecol Oncol 29(6):e99PubMedPubMedCentralCrossRefGoogle Scholar
  34. Wang S, Ni B, Zhang Z, Wang C, Wo L, Zhou C, Zhao Q, Zhao E (2019) Long non-coding RNA DNM3OS promotes tumor progression and EMT in gastric cancer by associating with snail. Biochem Biophys Res Commun 511(1):57–62PubMedCrossRefGoogle Scholar
  35. Winham SJ, Larson NB, Armasu SM, Fogarty ZC, Larson MC, McCauley B, Wang C, Lawrenson K, Gayther S, Cunningham JM, Fridley BL, Goode EL (2019) Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer. Hum Mol Genet 28(8):1331–1342PubMedCrossRefGoogle Scholar
  36. Yan R, Yang T, Zhai H, Zhou Z, Gao L, Li Y (2018) MicroRNA-150-5p affects cell proliferation, apoptosis, and EMT by regulation of the BRAF(V600E) mutation in papillary thyroid cancer cells. J Cell Biochem 119(11):8763–8772PubMedCrossRefGoogle Scholar
  37. Yin J, Hu W, Pan L, et al. let7 and miR17 promote selfrenewal and drive gefitinib resistance in nonsmall cell lung cancer. Oncol Rep. 2019Google Scholar
  38. Yu G, Jia B, Cheng Y, Zhou L, Qian B, Liu Z, Wang Y (2017) MicroRNA-429 sensitizes pancreatic cancer cells to gemcitabine through regulation of PDCD4. Am J Transl Res 9(11):5048–5055PubMedPubMedCentralGoogle Scholar
  39. Zhan L, Li J, Wei B (2018) Long non-coding RNAs in ovarian cancer. J Exp Clin Cancer Res 37(1):120PubMedPubMedCentralCrossRefGoogle Scholar
  40. Zhang R, Xia T (2017) Long non-coding RNA XIST regulates PDCD4 expression by interacting with miR-21-5p and inhibits osteosarcoma cell growth and metastasis. Int J Oncol 51(5):1460–1470PubMedPubMedCentralCrossRefGoogle Scholar
  41. Zhang Y, Hagedorn CH, Wang L (2011) Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta 1812(8):893–908PubMedCrossRefGoogle Scholar
  42. Zhang GW, Tian X, Li Y, Wang ZQ, Li XD, Zhu CY (2018a) Down-regulation of ETS2 inhibits the invasion and metastasis of renal cell carcinoma cells by inducing EMT via the PI3K/Akt signaling pathway. Biomed Pharmacother 104:119–126PubMedCrossRefGoogle Scholar
  43. Zhang Q, Chen B, Liu P et al (2018b) XIST promotes gastric cancer (GC) progression through TGF-beta1 via targeting miR-185. J Cell Biochem 119(3):2787–2796PubMedCrossRefGoogle Scholar
  44. Zheng R, Lin S, Guan L, Yuan H, Liu K, Liu C, Ye W, Liao Y, Jia J, Zhang R (2018) Long non-coding RNA XIST inhibited breast cancer cell growth, migration, and invasion via miR-155/CDX1 axis. Biochem Biophys Res Commun 498(4):1002–1008PubMedCrossRefGoogle Scholar
  45. Zhong Y, Gao D, He S, Shuai C, Peng S (2016) Dysregulated expression of long noncoding RNAs in ovarian cancer. Int J Gynecol Cancer 26(9):1564–1570PubMedPubMedCentralCrossRefGoogle Scholar
  46. Zhu J, Han S (2019) miR-150-5p promotes the proliferation and epithelial-mesenchymal transition of cervical carcinoma cells via targeting SRCIN1. Pathol Res Pract 215(4):738–747PubMedCrossRefGoogle Scholar
  47. Zou Y, Li S, Li Z, Song D, Zhang S, Yao Q (2019) MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-beta1 mediated epithelial-mesenchymal transition in hepatocytes. Cell Signal 58:1–8PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of ImagingProvincial Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.Department of OncologyProvincial Hospital Affiliated to Shandong UniversityJinanChina

Personalised recommendations