Advertisement

Gastric Cancer

, Volume 22, Issue 2, pp 302–313 | Cite as

Downregulation of miR-142-5p promotes tumor metastasis through directly regulating CYR61 expression in gastric cancer

  • Jing Yan
  • Bing Yang
  • Shuye Lin
  • Rui XingEmail author
  • Youyong LuEmail author
Original Article

Abstract

Background

Recurrence is a primary cause of gastric cancer (GC)-related deaths. We reported previously that low expression of miR-142-5p could predict recurrence in GC. The present study aimed to investigate the function and mechanism of miR-142-5p in metastasis of GC.

Methods

MiR-142-5p expression was detected in 101 GC samples by qRT-PCR. Its clinical significance was statistically analyzed. The roles of miR-142-5p and its candidate target gene CYR61 in metastasis were determined both in vivo and in vitro.

Results

MiR-142-5p downregulation was significantly associated with the recurrence (P = 0.031) and poor prognosis of GC (P = 0.043). MiR-142-5p inhibited cancer cell migration and invasion both in vitro and in vivo. CYR61 was identified as a novel direct target of miR-142-5p by bioinformatics analysis of target prediction and luciferase reporter assay. The re-expression and knockdown of CYR61 could, respectively, rescue the effects induced by miR-142-5p overexpression and knockdown. MiR-142-5p attenuated GC cell migration and invasion, at least partially, by inactivation of the canonical Wnt/β-catenin signaling pathway through CYR61.

Conclusions

The newly identified miR-142-5p-CYR61-Wnt/β-catenin axis partially illustrates the molecular mechanism of GC recurrence and represents a novel prognosis biomarker for GC.

Keywords

Gastric cancer MicroRNA-142-5p Cyr61 Prognosis Metastasis 

Notes

Acknowledgements

This study was supported by National Key Research and Development Program of China (2017YFC1308900), Beijing Municipal Commission of Health and Family Planning Project (PXM2018_026279_000005), National Natural Science Foundation of China (81572346, 81772502), Beijing Natural Science Foundation (7182027), National Bio-Tech 863 Program (No. 2012AA02A203), Beijing Nova Program (Z151100000315069), Beijing Talent Fund, and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201701).

Compliance with ethical standards

Ethics approval

This study was conducted with the approval of the Institutional Ethical Standards Committee.

Conflict of interest

The authors declare that there is no conflict of interest.

Human rights statement and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed.

Supplementary material

10120_2018_872_MOESM1_ESM.pdf (3.5 mb)
Figure S1. The effects of miR-142-5p on the expression of EMT related markers in AGS cells; Figure S2. Effects of miR-142-5p on cell proliferation and effects of CYR61 on cell migration and invasion in GC cells in vitro. (A) Left and middle, cell proliferation was remarkably inhibited in miR-142-5p-overexpressing BGC823 and SGC7901 cells respectively compared with control cells by MTT assay. Right, cell proliferation was remarkably upregulated in miR-142-5p inhibitor-transfected AGS cells compared with control cells by MTT assay. (B) Left, Western blot detected the CYR61 expression after transfecting CYR61 in the AGS cells. Middle, transwell assay showed that the migration and invasion were significantly upregulated in CYR61-overexpressing AGS cells compared with control cells. Right, the quantification results of migrated cells and invaded cells through membrane were plotted, respectively. (C, D) Left: western blot detected the CYR61 expression after transfection of shRNA for CYR61 in the BGC823 (C) and SGC7901 (D) cells. Middle: cell migration (upprer) and invasion (lower) through membrane were remarkably downregulated after downregulation of CYR61 expression in BGC823 (C) and SGC7901 (D) cells respectively compared with control cells. Right, the quantification results of migrated cells and invaded cells through membrane were plotted, respectively. ** P < 0.01, *** P < 0.001; Figure S3. The effects of CYR61 on cell proliferation, migration and invasion in GES1 cells. (A) Western blot detected the CYR61 expression after transfecting CYR61 in GES1 cells. (B) MTT assay detected the effect of CYR61 on cell proliferation. (C) Left, cell migration (upper) and invasion (lower) were remarkably upregulated in CYR61 overexpressed GES1 cells compared with control cells. Right, the quantification of migrated cells and invaded cells through membrane were plotted, respectively, * P < 0.05, ** P < 0.01 (PDF 3575 KB)
10120_2018_872_MOESM2_ESM.docx (37 kb)
Supplementary material 2 (DOCX 37 KB)

References

  1. 1.
    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer JClin. 2016;66:115–32.CrossRefGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  3. 3.
    Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries. Lancet. 2015;385:977–1010.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang X, Yan Z, Zhang J, Gong L, Li W, Cui J, et al. Combination of hsa-miR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection. Ann Oncol. 2011;22:2257–66.CrossRefPubMedGoogle Scholar
  5. 5.
    Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2015;2015:852–63.CrossRefGoogle Scholar
  6. 6.
    Paez D, Labonte MJ, Bohanes P, Zhang W, Benhaim L, Ning Y, et al. Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res. 2012;18:645–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Liu Y, Xing R, Zhang X, Dong W, Zhang J, Yan Z, et al. MiR-375 targets the p53 gene to regulate cellular response to ionizing radiation and etoposide in gastric cancer cells. DNA Repair. 2013;12:741–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Shrestha A, Mukhametshina RT, Taghizadeh S, Vásquez-Pacheco E, Cabrera-Fuentes H, Rizvanov A, et al. MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease. Dev Dyn. 2017;246:285–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Shaojun Liu Z, Xiao F, Ai F, Liu X, Chen K, Cao, et al. MiR-142-5p promotes development of colorectal cancer through targeting SDHB and facilitating generation of aerobic glycolysis. Biomed Pharmacother. 2017;92:1119–27.CrossRefPubMedGoogle Scholar
  10. 10.
    Ma Z, Liu T, Huang W, Liu H, Zhang H-M, Li Q, et al. MicroRNA regulatory pathway analysis identifies miR-142-5p as a negative regulator of TGF-β pathway via targeting SMAD3. Oncotarget. 2016;7:71504–13.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Saito Y, Suzuki H, Tsugawa H, Imaeda H, Matsuzaki J, Hirata K, et al. Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication. PLoS One. 2012;7:e47396.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tsang FH, Au SL, Wei L, Fan DN, Lee JM, Wong CC, et al. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility. Front Med. 2015;9:331–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Segura MF, Belitskaya-Levy I, Rose AE, Zakrzewski J, Gaziel A, Hanniford D, et al. Melanoma MicroRNA signature predicts post-recurrence survival. Clin Cancer Res. 2010;16:1577–86.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang JX, Xu Y, Gao Y, Chen C, Zheng ZS, Yun M, et al. Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway. Mol Cancer. 2017;16:18.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hou CG, Luo XY, Li G. Diagnostic and prognostic value of serum miR-206 in patients with gastric cancer. Cell Physiol Biochem. 2016;39:1512–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Han TS, Hur K, Xu G, Choi B, Okugawa Y, Toiyama Y, et al. MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1. Gut. 2015;64:203–14.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu X, Sempere LF, Galimberti F, Freemantle SJ, Black C, Dragnev KH, et al. Uncovering growth-suppressive microRNAs in lung cancer. Clin Cancer Res. 2009;15:1177–83.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Harris LG, Pannell LK, Singh S, Samant RS, Shevde LA. Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene. 2012;31:3370–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, et al. Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation. Cancer Res. 2010;70:2932–41.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, et al. CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. Cancer Res. 2008;68:7323–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Lau LF. CCN1/CYR61: the very model of a modern matricellular protein. Cell Mol Life Sci. 2011;68:3149–63.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nguyen N, Kuliopulos A, Graham RA, Covic L. Tumor-derived Cyr61 promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Res. 2006;66:2658–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Lin MT, Chang CC, Lin BR, Yang HY, Chu CY, et al. Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin alpha2beta1. J Biol Chem. 2007;282:34594–604.CrossRefPubMedGoogle Scholar
  24. 24.
    Han S, Bui NT, Ho MT, Kim YM, Cho M, Shin DB. Dexamethasone inhibits TGF-β1-induced cell migration by regulating the ERK and AKT pathways in human colon cancer cells via CYR61. Cancer Res Treat. 2016;48:1141–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Hesler RA, Huang JJ, Starr MD, Treboschi VM, Bernanke AG, Nixon AB, et al. TGF-β1-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. Carcinogenesis. 2016;37:1041–51.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, et al. Wnt/β-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10:101.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xiangjun Tong JO’Kelly, Xie D, Mori A, Lemp N, McKenna R, et al. Cyr61 suppresses the growth of non-small-cell lung cancer cells via the β-catenin-c-myc-p53 pathway. Oncogene. 2004;23:4847–55.CrossRefPubMedGoogle Scholar
  28. 28.
    Sano M, Wilfredo DRDriscoll, DeJesus-Monge E, Quattrochi B, Appleman VA, et al. Activation of WNT/β-catenin signaling enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61. Neoplasia. 2016;18:785–94.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Isobe T, Hisamori S, Hogan DJ, Zabala M, Hendrickson DG, Dalerba P, et al. MiR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife. 2014;3:e01977.CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Weike Si Q, Kang HH, Luu JK, Park Q, Luo W-X, Song, et al. CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol. 2006;26:2955–64.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  1. 1.Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital and InstituteBeijingChina

Personalised recommendations