Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-01-2020 | Rectal Cancer | Original Article – Cancer Research

High expression of microRNA-199a-5p is associated with superior clinical outcomes in patients with locally advanced rectal cancer

Authors: Dong Won Baek, Gyeonghwa Kim, Byung Woog Kang, Hye Jin Kim, Su Yeon Park, Jun Seok Park, Gyu-Seog Choi, Min Kyu Kang, Keun Hur, Jong Gwang Kim

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2020

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.

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

Kapur P (2011) Tailoring treatment of rectal adenocarcinoma: immunohistochemistry for predictive biomarkers. Anticancer Drugs 22:362–370. https://doi.org/10.1097/CAD.0b013e3283433764 CrossRefPubMed

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 CrossRefPubMed

Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385. https://doi.org/10.1038/nrm1644 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 33:541–547PubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Title: High expression of microRNA-199a-5p is associated with superior clinical outcomes in patients with locally advanced rectal cancer
Authors: Dong Won Baek
Gyeonghwa Kim
Byung Woog Kang
Hye Jin Kim
Su Yeon Park
Jun Seok Park
Gyu-Seog Choi
Min Kyu Kang
Keun Hur
Jong Gwang Kim
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keywords: Rectal Cancer
Rectal Cancer
Biomarkers
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-03099-4

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

High expression of microRNA-199a-5p is associated with superior clinical outcomes in patients with locally advanced rectal cancer

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Evolving the pulmonary nodules diagnosis from classical approaches to deep learning-aided decision support: three decades’ development course and future prospect

High density of CD66b in primary high-grade ovarian cancer independently predicts response to chemotherapy

18F-FDG PET/CT versus CT/MR imaging for detection of neck lymph node metastasis in palpably node-negative oral cavity cancer

Herbal nutraceuticals: safe and potent therapeutics to battle tumor hypoxia

Candidate lncRNA–miRNA–mRNA network in predicting hepatocarcinogenesis with cirrhosis: an integrated bioinformatics analysis

A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab-based therapy

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page