Tumor Biology

, Volume 37, Issue 12, pp 15649–15663 | Cite as

Establishment of a miRNA-mRNA regulatory network in metastatic renal cell carcinoma and screening of potential therapeutic targets

  • Jie Zhu
  • Xin Ma
  • Yu Zhang
  • Dong Ni
  • Qing Ai
  • Hongzhao Li
  • Xu Zhang
Original Article

Abstract

This study aimed to screen effective diagnosis or treatment biomarkers for renal cell carcinoma, especially for metastatic renal cell carcinoma (mRCC) based on microRNA (miRNA) and messenger RNA (mRNA) genechip, and their regulatory network. The differential expressions of miRNAs and mRNAs were examined by miRNA and mRNA gene-chip analyses, respectively, in patients with either localized renal cell carcinoma (lRCC) or mRCC, and a miRNA-mRNA regulatory network was established. Subsequently, the regulation of selected mRNAs by miRNAs was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and dual-luciferase reporter gene assay. Thirty-one up-regulated miRNAs, 196 down-regulated miRNAs, 214 up-regulated mRNAs, and 156 down-regulated mRNAs were identified in patients with mRCC. In total, 1315 miRNA-mRNA pairs, involving 34 miRNAs and 225 mRNAs, were established. The expression profiles of four up-regulated miRNAs, hsa-miR-139-5p, hsa-miR-140-3p, hsa-miR-151a-3p, and hsa-miR-204-5p, and four down-regulated miRNAs, hsa-miR-409-3p, hsa-miR-671-3p, hsa-miR-1203, and hsa-miR-1290, were consistent with the results from the miRNA gene-chip analysis. The expression profiles of NEU2, MASP1, MCL1, ARHGAP11A, HOXA1, and CLDN8 were consistent with the results from the mRNA gene-chip analysis. In vitro, hsa-miR-140-3p bound to the 3′ untranslated region (3′-UTR) of the MASP1 mRNA and down-regulated its expression. Similarly, hsa-miR-151a-3p, hsa-miR-671-3p, and hsa-miR-1290 bound to the 3′-UTRs of the MCL1, HOXA1, and HOXA1 mRNAs, respectively, and down-regulated their expressions. However, binding by hsa-miR-140-3p, hsa-miR-671-3p, or hsa-miR-1290 did not down-regulate the expressions of NEU2, ARHGAP11A, and CLDN8, respectively. This study provides a significant reference of investigating the pathogenesis of mRCC and the subsequent screening of potential therapeutic targets.

Keywords

Localized renal cell carcinoma Metastatic renal cell carcinoma Genechip Regulatory network Molecular target Screening 

Notes

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (no. 81100483) and the National High Technology Research and Development Program of China (863 program; no. 2012AA021100).

References

  1. 1.
    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
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Chow WH, Devesa SS, Warren JL, Fraumeni Jr JF. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281:1628–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Fenaux P, Haase D, Sanz GF, Santini V, Buske C. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii57–69.CrossRefPubMedGoogle Scholar
  5. 5.
    Glynne-Jones R, Nilsson PJ, Aschele C, Goh V, Peiffert D, Cervantes A, Arnold D. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol. 2014;40:1165–76.CrossRefPubMedGoogle Scholar
  6. 6.
    Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii21–26.Google Scholar
  7. 7.
    Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U, Ladetto M. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii76–82.CrossRefPubMedGoogle Scholar
  8. 8.
    Bozkurt O, Karaca H, Hacibekiroglu I, Kaplan MA, Duzkopru Y, Uysal M, Berk V, Inanc M, Duran AO, Ozaslan E, Ucar M, Ozkan M. Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients? J Chemother. 2015;1973947815Y0000000039.Google Scholar
  9. 9.
    Diekstra MH, Swen JJ, Boven E, Castellano D, Gelderblom H, Mathijssen RH, Rodriguez-Antona C, Garcia-Donas J, Rini BI, Guchelaar HJ. Cyp3a5 and abcb1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. Eur Urol. 2015.Google Scholar
  10. 10.
    Miyazaki A, Miyake H, Harada K, Fujisawa M. No significant correlation of clinical outcomes between first- and second-line tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma. Anticancer Res. 2015;35:3067–73.PubMedGoogle Scholar
  11. 11.
    Laitinen M, Parry M, Ratasvuori M, Wedin R, Albergo JI, Jeys L, Abudu A, Carter S, Gaston L, Tillman R, Grimer R. Survival and complications of skeletal reconstructions after surgical treatment of bony metastatic renal cell carcinoma. Eur J Surg Oncol. 2015.Google Scholar
  12. 12.
    Bodnar L, Stec R, Cierniak S, Synowiec A, Wcislo G, Jesiotr M, Koktysz R, Kozlowski W, Szczylik C. Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines. Ann Oncol. 2015.Google Scholar
  13. 13.
    Abdallah AO, Vallurupalli S, Kunthur A. Pazopanib- and bevacizumab-induced reversible heart failure in a patient with metastatic renal cell carcinoma: a case report. J Oncol Pharm Pract. 2015.Google Scholar
  14. 14.
    Lamuraglia M, Raslan S, Elaidi R, Oudard S, Escudier B, Slimane K, Penna RR, Wagner M, Lucidarme O. mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response. Eur Radiol. 2015.Google Scholar
  15. 15.
    Wang CH, Zhao TX, Li M, Zhang C, Xing XH. Characterization of a novel acinetobacter baumannii xanthine dehydrogenase expressed in Escherichia coli. Biotechnol Lett. 2015.Google Scholar
  16. 16.
    Wu D, Gantier MP. Normalization of affymetrix miRNA microarrays for the analysis of cancer samples. Methods Mol Biol. 2015.Google Scholar
  17. 17.
    Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, Cuppen E. Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 2005;120:21–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704–14.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Juan D, Alexe G, Antes T, Liu H, Madabhushi A, Delisi C, Ganesan S, Bhanot G, Liou LS. Identification of a microRNA panel for clear-cell kidney cancer. Urology. 2010;75:835–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Yi Z, Fu Y, Zhao S, Zhang X, Ma C. Differential expression of miRNA patterns in renal cell carcinoma and nontumorous tissues. J Cancer Res Clin Oncol. 2010;136:855–62.CrossRefPubMedGoogle Scholar
  21. 21.
    Qiu ZL, Shen CT, Song HJ, Wei WJ, Luo QY. Differential expression profiling of circulation microRNAs in PTC patients with non-(131)i and (131)i-avid lungs metastases: a pilot study. Nucl Med Biol. 2015;42:499–504.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang J, Liu Y, Liu Z, Wang XM, Yin DT, Zheng LL, Zhang DY, Lu XB. Differential expression profiling and functional analysis of microRNAs through stage I-III papillary thyroid carcinoma. Int J Med Sci. 2013;10:585–92.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Chow TF, Youssef YM, Lianidou E, Romaschin AD, Honey RJ, Stewart R, Pace KT, Yousef GM. Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem. 2010;43:150–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Butz H, Szabo PM, Khella HW, Nofech-Mozes R, Patocs A, Yousef GM. MiRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. Oncotarget. 2015;6:12543–57.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wittekind C, Oberschmid B. TNM classification of malignant tumors 2010: general aspects and amendments in the general section. Pathologe. 2010;31:333–4 .336-338CrossRefPubMedGoogle Scholar
  26. 26.
    Wittekind C. 2010 TNM system: on the 7th edition of TNM classification of malignant tumors. Pathologe. 2010;31:331–2.CrossRefPubMedGoogle Scholar
  27. 27.
    Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455:58–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Tili E, Michaille JJ, Wernicke D, Alder H, Costinean S, Volinia S, Croce CM. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci U S A. 2011;108:4908–13.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sinha S, Dutta S, Datta K, Ghosh AK, Mukhopadhyay D. Von Hippel-Lindau gene product modulates tis11b expression in renal cell carcinoma: impact on vascular endothelial growth factor expression in hypoxia. J Biol Chem. 2009;284:32610–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Majid S, Saini S, Dar AA, Hirata H, Shahryari V, Tanaka Y, Yamamura S, Ueno K, Zaman MS, Singh K, Chang I, Deng G, Dahiya R. MicroRNA-205 inhibits SRC-mediated oncogenic pathways in renal cancer. Cancer Res. 2011;71:2611–21.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jung M, Mollenkopf HJ, Grimm C, Wagner I, Albrecht M, Waller T, Pilarsky C, Johannsen M, Stephan C, Lehrach H, Nietfeld W, Rudel T, Jung K, Kristiansen G. MicroRNA profiling of clear cell renal cell cancer identifies a robust signature to define renal malignancy. J Cell Mol Med. 2009;13:3918–28.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tan X, Qin W, Zhang L, Hang J, Li B, Zhang C, Wan J, Zhou F, Shao K, Sun Y, Wu J, Zhang X, Qiu B, Li N, Shi S, Feng X, Zhao S, Wang Z, Zhao X, Chen Z, Mitchelson K, Cheng J, Guo Y, He J. A 5-microRNA signature for lung squamous cell carcinoma diagnosis and HSA-miR-31 for prognosis. Clin Cancer Res. 2011;17:6802–11.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Jie Zhu
    • 1
  • Xin Ma
    • 1
  • Yu Zhang
    • 1
  • Dong Ni
    • 1
  • Qing Ai
    • 1
  • Hongzhao Li
    • 1
  • Xu Zhang
    • 1
  1. 1.Department of UrologyChinese People’s Liberation Army General HospitalBeijingChina

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