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The Profile of Serum microRNAs Predicts Prognosis for Resected Gastric Cancer Patients Receiving Platinum-Based Chemotherapy

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Abstract

Background and Aim

Adjuvant chemotherapy is an important component in the treatment of gastric cancer (GC) patients; however, some patients do not respond to the drugs. We aimed to develop a practical profile based on serum microRNAs (miRNAs) that can be used to predict patients likely to respond to treatment.

Methods

Microarrays were used to screen cisplatin-resistant SGC7901/DDP GC cells and the parental SGC7901 cell lines for miRNAs related to chemotherapy sensitivity. The correlation between the expression patterns of identified serum miRNAs and overall survival was confirmed in 68 GC patients. Furthermore, we also validated the signature of the serum miRNAs in an independent cohort of 50 GC patients.

Results

From the screening microarrays, we focused on miR-15a, miR-15b and miR-93 as downregulated miRNAs in the SGC7901/DDP cells and miR-27a, miR-106a and miR-664 as upregulated miRNAs. Only serum miR-106, miR-15a, miR-93 and miR-664 were useful in predicting the prognosis of patients who received adjuvant chemotherapy. We identified a signature of four serum miRNAs (miR-106, miR-15a, miR-93 and miR-664) that, when combined, can be used as a risk score for overall survival. Patients with a higher risk score had worse prognosis (p < 0.05). For the independent cohort of patients, the signature of the four miRNAs predicted prognosis well.

Conclusion

Our data showed that the risk score derived from the four serum miRNAs was closely associated with the overall survival in GC patients who received adjuvant chemotherapy.

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References

  1. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–456.

    Article  CAS  PubMed  Google Scholar 

  2. Bang YJ, Kim YW, Kim YW, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–321.

    Article  CAS  PubMed  Google Scholar 

  3. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

    Article  CAS  PubMed  Google Scholar 

  4. Macdonald JS, Gohmann JJ. Chemotherapy of advanced gastric cancer: present status, future prospects. Semin Oncol. 1988;15:42–49.

    CAS  PubMed  Google Scholar 

  5. Kim CH, Kim HK, Rettig RL, et al. MiRNA signature associated with outcome of gastric cancer patients following chemotherapy. BMC Med Genomics. 2011;4:79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang XL, Shi HJ, Wang JP, et al. MicroRNA-218 is upregulated in gastric cancer after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and increases chemosensitivity to cisplatin. World J Gastroenterol. 2014;20:11347–11355.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Huang ZH, Hua D, Du X. Polymorphisms in p53, GSTP1 and XRCC1 predict relapse and survival of gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy. Cancer Chemother Pharmacol. 2009;64:1001–1007.

    Article  CAS  PubMed  Google Scholar 

  8. Teng KY, Qiu MZ, Li ZH, et al. DNA polymerase eta protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy. J Transl Med. 2010;8:126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baek SK, Kim SY, Lee JJ, et al. Increased ERCC expression correlates with improved outcome of patients treated with cisplatin as an adjuvant therapy for curatively resected gastric cancer. Cancer Res Treat. 2006;38:19–24.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Huang Y, Shen XJ, Zou Q, et al. Biological functions of microRNAs: a review. J Physiol Biochem. 2011;67:129–139.

    Article  CAS  PubMed  Google Scholar 

  11. Chan E, Prado DE, Weidhaas JB. Cancer microRNAs: from subtype profiling to predictors of response to therapy. Trends Mol Med. 2011;17:235–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baker M. RNA interference: MicroRNAs as biomarkers. Nature. 2010;464:1227.

    Article  CAS  PubMed  Google Scholar 

  13. Cortez MA, Bueso-Ramos C, Ferdin J, et al. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8:467–477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wright GW, Simon RM. A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003;19:2448–2455.

    Article  CAS  PubMed  Google Scholar 

  15. Schlitt T, Palin K, Rung J, et al. From gene networks to gene function. Genome Res. 2003;13:2568–2576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Draghici S, Khatri P, Tarca TL, et al. A systems biology approach for pathway level analysis. Genome Res. 2007;17:1537–1545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shalgi R, Lieber D, Oren M, Pilpel Y. Global and local architecture of the mammalian microRNA-transcription factor regulatory network. Plos Comput Biol. 2007;3:e131.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Joung JG, Hwang KB, Nam JW, Kim SJ, Zhang BT. Discovery of microRNA-mRNA modules via population-based probabilistic learning. Bioinformatics. 2007;23:1141–1147.

    Article  CAS  PubMed  Google Scholar 

  19. Cimmino A, Calin GA, Fabbri M, et al. MiR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2006;103:2464.

    Article  CAS  Google Scholar 

  20. Pouliot LM, Chen YC, Bai J, et al. Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family. Cancer Res. 2012;72:5945–5955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Druz A, Chen YC, Guha R, et al. Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. RNA Biol. 2013;10:287–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xia L, Zhang D, Du R, et al. MiR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 2008;123:372–379.

    Article  CAS  PubMed  Google Scholar 

  23. Fontana L, Fiori ME, Albini S, et al. Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. Plos ONE. 2008;3:e2236.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jiang P, Rao EY, Meng N, Zhao Y, Wang JJ. MicroRNA-17-92 significantly enhances radioresistance in human mantle cell lymphoma cells. Radiat Oncol. 2010;5:100.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Huang D, Wang H, Liu R, et al. MiRNA27a is a biomarker for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer. J Cell Biochem. 2014;115:549–556.

    Article  CAS  PubMed  Google Scholar 

  26. Pouliot LM, Chen YC, Bai J, et al. Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family. Cancer Res. 2012;72:5945–5955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xia L, Zhang D, Du R, et al. MiR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 2008;123:372–379.

    Article  CAS  PubMed  Google Scholar 

  28. Zhao Z, Zhang L, Yao Q, Tao Z: MiR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells. Cancer Gene Ther. 2015.

  29. Calin GA, Cimmino A, Fabbri M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. PNAS. 2008;105:5166–5171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rao E, Jiang C, Ji M, et al. The miRNA-17 approximately 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3 K/AKT pathway activation. Leukemia. 2012;26:1064–1072.

    Article  CAS  PubMed  Google Scholar 

  31. Kim YW, Kim EY, Jeon D, et al. Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells. Drug Des Devel Ther. 2014;8:293–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang Y, Lu Q, Cai X. MicroRNA-106a induces multidrug resistance in gastric cancer by targeting RUNX3. FEBS Lett. 2013;587:3069–3075.

    Article  CAS  PubMed  Google Scholar 

  33. Huh JH, Kim TH, Kim K, et al. Dysregulation of miR-106a and miR-591 confers paclitaxel resistance to ovarian cancer. Br J Cancer. 2013;109:452–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mendell JT. MiRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008;133:217–222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li J, Wang Y, Song Y, Fu Z, Yu W. MiR-27a regulates cisplatin resistance and metastasis by targeting RKIP in human lung adenocarcinoma cells. Mol Cancer. 2014;13:193.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Huang D, Wang H, Liu R, et al. MiRNA27a is a biomarker for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer. J Cell Biochem. 2014;115:549–556.

    Article  CAS  PubMed  Google Scholar 

  37. Chen Z, Ma T, Huang C, et al. MiR-27a modulates the MDR1/P-glycoprotein expression by inhibiting FZD7/beta-catenin pathway in hepatocellular carcinoma cells. CELL SIGNAL. 2013;25:2693–2701.

    Article  CAS  PubMed  Google Scholar 

  38. Feng DD, Zhang H, Zhang P, et al. Down-regulated miR-331-5p and miR-27a are associated with chemotherapy resistance and relapse in leukaemia. J CELL MOL MED. 2011;15:2164–2175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen L, Jiang M, Yuan W, Tang H. Prognostic value of miR-93 overexpression in resectable gastric adenocarcinomas. Acta Gastroenterol Belg. 2012;75:22–27.

    PubMed  Google Scholar 

  40. Liu S, Patel SH, Ginestier C, et al. MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLOS GENET. 2012;8:e1002751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang IP, Tsai HL, Hou MF, et al. MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle. CARCINOGENESIS. 2012;33:1522–1530.

    Article  CAS  PubMed  Google Scholar 

  42. Xiao ZG, Deng ZS, Zhang YD, Zhang Y, Huang ZC. Clinical significance of microRNA-93 downregulation in human colon cancer. Eur J Gastroenterol Hepatol. 2013;25:296–301.

    Article  CAS  PubMed  Google Scholar 

  43. Song J, Bai Z, Zhang J, et al. Serum microRNA-21 levels are related to tumor size in gastric cancer patients but cannot predict prognosis. Oncol Lett. 2013;6:1733–1737.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ohshima K, Inoue K, Fujiwara A, et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLOS ONE. 2010;5:e13247.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Fabbri M, Paone A, Calore F, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci. 2012;109:E2110–E2116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shivapurkar N, Weiner LM, Marshall JL, et al. Recurrence of early stage colon cancer predicted by expression pattern of circulating microRNAs. Plos One. 2014;9:e84686.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Summerer I, Niyazi M, Unger K, et al. Changes in circulating microRNAs after radiochemotherapy in head and neck cancer patients. Radiat Oncol. 2013;8:296.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

The Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding. Rising Star program of Beijing Friendship Hospital, CMU.

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Correspondence to Zhongtao Zhang.

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We declare that we have no financial or personal relationships with other people or organizations who could inappropriately influence our work.

Additional information

Jianning Song and Jie Yin have contributed equally to this work.

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Song, J., Yin, J., Bai, Z. et al. The Profile of Serum microRNAs Predicts Prognosis for Resected Gastric Cancer Patients Receiving Platinum-Based Chemotherapy. Dig Dis Sci 62, 1223–1234 (2017). https://doi.org/10.1007/s10620-017-4513-2

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  • DOI: https://doi.org/10.1007/s10620-017-4513-2

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