Abstract
Purpose
We aimed to identify biomarkers of response to preoperative CRT in patients with LARC using comprehensive miRNA analysis.
Methods
This study included 65 rectal cancer specimens and 89 serum samples from patients diagnosed with LARC and treated with preoperative. All specimens were collected before CRT for evaluation of biologic differences between the good and poor CRT response groups (ypStage 0/I versus II/III/IV). For specific miRNA discovery, 800 miRNAs in 20 rectal cancer specimens were analyzed with a NanoString assay. For validation, a total of 65 tissue and 89 serum samples were tested with reverse transcription-polymerase chain reaction (RT-PCR).
Results
In the discovery set, 16 target miRNAs were detected. In the validation set, higher expression of three miRNAs (miR-199a/b-3p, miR-199a-5p, and miR-199b-5p) was significantly associated with better response to CRT. In the univariate survival analysis, upregulation of these three miRNAs was associated with superior relapse-free survival (RFS) and overall survival (OS). Meanwhile, only a higher level of tissue miR-199a-5p was associated with superior RFS [hazard ratio (HR), 0.0.91; 95% confidence interval (CI) 0.035–0.580; p = 0.002] and OS (HR, 0.272; 95% CI 0.023–0.658; p < 0.001) in the multivariate survival analysis. Also, a higher level of exosomal miR-199b-5p correlated with better response to CRT (p = 0.0397).
Conclusion
High expression of tissue miR-199a/b-3p, miR-199a-5p, and miR-199b-5p was significantly associated with response to CRT, and a high level of tissue miR-199a-5p was associated with superior survival outcomes. Also, upregulated exosomal miR-199b-5p correlated with CRT response, reflecting its promise as a circulating biomarker of CRT response in patients with LARC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bosset JF et al (2005) Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol 23:5620–5627. https://doi.org/10.1200/jco.2005.02.113
Chetty R et al (2012a) Pathological grading of regression: an international study group perspective. J Clin Pathol 65:865–866. https://doi.org/10.1136/jclinpath-2012-201054
Chetty R et al (2012b) International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol 43:1917–1923. https://doi.org/10.1016/j.humpath.2012.01.020
Conde-Muino R, Cuadros M, Zambudio N, Segura-Jimenez I, Cano C, Palma P (2015) Predictive biomarkers to chemoradiation in locally advanced rectal cancer. Biomed Res Int 2015:921435. https://doi.org/10.1155/2015/921435
D’Angelo E et al (2016) Serum miR-125b is a non-invasive predictive biomarker of the pre-operative chemoradiotherapy responsiveness in patients with rectal adenocarcinoma. Oncotarget 7:28647–28657. https://doi.org/10.18632/oncotarget.8725
De Caluwe L, Van Nieuwenhove Y, Ceelen WP (2013) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd006041.pub3
Della Vittoria Scarpati G et al (2012) A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 83:1113–1119. https://doi.org/10.1016/j.ijrobp.2011.09.030
Edge SB, Compton CC (2010) The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17:1471–1474. https://doi.org/10.1245/s10434-010-0985-4
Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269. https://doi.org/10.1038/nrc1840
Fokas E et al (2014) Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 32:1554–1562. https://doi.org/10.1200/jco.2013.54.3769
Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr (2018) Total neoadjuvant therapy: a shifting paradigm in locally advanced rectal cancer management. Clin Colorectal Cancer 17:1–12. https://doi.org/10.1016/j.clcc.2017.06.008
Gaur A et al (2007) Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67:2456–2468. https://doi.org/10.1158/0008-5472.CAN-06-2698
Hotchi M et al (2013) MicroRNA expression is able to predict response to chemoradiotherapy in rectal cancer. Mol Clin Oncol 1:137–142. https://doi.org/10.3892/mco.2012.9
Huang GH, Shan H, Li D, Zhou B, Pang PF (2017) MiR-199a-5p suppresses tumorigenesis by targeting clathrin heavy chain in hepatocellular carcinoma. Cell Biochem Funct 35:98–104. https://doi.org/10.1002/cbf.3252
Hur K, Toiyama Y, Okugawa Y, Ide S, Imaoka H, Boland CR, Goel A (2017) Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer. Gut 66:654–665. https://doi.org/10.1136/gutjnl-2014-308737
Jo P et al (2017) Changes of microrna levels in plasma of patients with rectal cancer during chemoradiotherapy. Int J Mol Sci. https://doi.org/10.3390/ijms18061140
Kapur P (2011) Tailoring treatment of rectal adenocarcinoma: immunohistochemistry for predictive biomarkers. Anticancer Drugs 22:362–370. https://doi.org/10.1097/CAD.0b013e3283433764
Kheirelseid EA et al (2013) miRNA expressions in rectal cancer as predictors of response to neoadjuvant chemoradiation therapy. Int J Colorectal Dis 28:247–260. https://doi.org/10.1007/s00384-012-1549-9
Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385. https://doi.org/10.1038/nrm1644
Krazinski BE et al (2019) Altered expression of DDR1 in clear cell renal cell carcinoma correlates with miR-199a/b-5p and patients’ outcome. Cancer Genom Proteom 16:179–193. https://doi.org/10.21873/cgp.20124
Kuremsky JG, Tepper JE, McLeod HL (2009) Biomarkers for response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 74:673–688. https://doi.org/10.1016/j.ijrobp.2009.03.003
Lee YR et al (2019) Circulating exosomal noncoding RNAs as prognostic biomarkers in human hepatocellular carcinoma. Int J Cancer 144:1444–1452. https://doi.org/10.1002/ijc.31931
Li Y, Wang D, Li X, Shao Y, He Y, Yu H, Ma Z (2019) MiR-199a-5p suppresses non-small cell lung cancer via targeting MAP3K11. J Cancer 10:2472–2479. https://doi.org/10.7150/jca.29426
Ludmir EB, Palta M, Willett CG, Czito BG (2017) Total neoadjuvant therapy for rectal cancer: an emerging option. Cancer 123:1497–1506. https://doi.org/10.1002/cncr.30600
Malumbres M (2013) miRNAs and cancer: an epigenetics view. Mol Aspects Med 34:863–874. https://doi.org/10.1016/j.mam.2012.06.005
Niemoeller OM, Niyazi M, Corradini S, Zehentmayr F, Li M, Lauber K, Belka C (2011) MicroRNA expression profiles in human cancer cells after ionizing radiation. Radiat Oncol 6:29. https://doi.org/10.1186/1748-717X-6-29
Pant S, Hilton H, Burczynski ME (2012) The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 83:1484–1494. https://doi.org/10.1016/j.bcp.2011.12.037
Revenfeld AL, Baek R, Nielsen MH, Stensballe A, Varming K, Jorgensen M (2014) Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. Clin Ther 36:830–846. https://doi.org/10.1016/j.clinthera.2014.05.008
Rödel C et al (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688–8696. https://doi.org/10.1200/JCO.2005.02.1329
Sauer R et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740. https://doi.org/10.1056/NEJMoa040694
Svoboda M, Izakovicova Holla L, Sefr R, Vrtkova I, Kocakova I, Tichy B, Dvorak J (2008) Micro-RNAs miR125b and miR137 are frequently upregulated in response to capecitabine chemoradiotherapy of rectal cancer. Int J Oncol 33:541–547
Svoboda M et al (2012) MicroRNA expression profile associated with response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. Radiat Oncol 7:195. https://doi.org/10.1186/1748-717X-7-195
Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110:13–21. https://doi.org/10.1016/j.ygyno.2008.04.033
Templin T, Paul S, Amundson SA, Young EF, Barker CA, Wolden SL, Smilenov LB (2011) Radiation-induced micro-RNA expression changes in peripheral blood cells of radiotherapy patients. Int J Radiat Oncol Biol Phys 80:549–557. https://doi.org/10.1016/j.ijrobp.2010.12.061
Trakarnsanga A, Ithimakin S, Weiser MR (2012) Treatment of locally advanced rectal cancer: controversies and questions. World J Gastroenterol 18:5521–5532. https://doi.org/10.3748/wjg.v18.i39.5521
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596
Wu A, Chen Y, Liu Y, Lai Y, Liu D (2018) miR-199b-5p inhibits triple negative breast cancer cell proliferation, migration and invasion by targeting DDR1. Oncol Lett 16:4889–4896. https://doi.org/10.3892/ol.2018.9255
Wulfken LM et al (2011) MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One 6:e25787. https://doi.org/10.1371/journal.pone.0025787
Xu L, Li M, Wang M, Yan D, Feng G, An G (2014) The expression of microRNA-375 in plasma and tissue is matched in human colorectal cancer. BMC Cancer 14:714. https://doi.org/10.1186/1471-2407-14-714
Zeng B, Shi W, Tan G (2018) MiR-199a/b-3p inhibits gastric cancer cell proliferation via down-regulating PAK4/MEK/ERK signaling pathway. BMC Cancer 18:34. https://doi.org/10.1186/s12885-017-3949-2
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (2014R1A5A2009242, 2017M3A9G8083382, 2019R1A2C1083892) and the Korean Cancer Foundation (K20180518).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest in regard to this study.
Ethical approval and consent to participate
All procedures in this study that involved human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Baek, D.W., Kim, G., Kang, B.W. et al. High expression of microRNA-199a-5p is associated with superior clinical outcomes in patients with locally advanced rectal cancer. J Cancer Res Clin Oncol 146, 105–115 (2020). https://doi.org/10.1007/s00432-019-03099-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-019-03099-4