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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

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Volume 56, Issue 6

Issues

High microRNA-28-5p expression in colorectal adenocarcinoma predicts short-term relapse of node-negative patients and poor overall survival of patients with non-metastatic disease

Panagiotis Tsiakanikas
  • Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
  • Other articles by this author:
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/ Christos K. Kontos
  • Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
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  • De Gruyter OnlineGoogle Scholar
/ Dimitrios Kerimis
  • Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
  • Other articles by this author:
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/ Iordanis N. Papadopoulos / Andreas Scorilas
  • Corresponding author
  • Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece, Phone: +30 2107274306, Fax: +30 2107274158
  • Email
  • Other articles by this author:
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Published Online: 2018-04-24 | DOI: https://doi.org/10.1515/cclm-2017-0430

Abstract

Background:

MicroRNAs (miRNAs) may function either as oncogenes or tumor suppressors and are heavily involved in the initiation and progression of cancer, and in metastasis of tumor cells. MicroRNA-28-5p (miR-28-5p) targets several cancer-related genes and is hence involved in cell proliferation, migration, invasion and epithelial-mesenchymal transition. In this study, we investigated the potential diagnostic and prognostic significance of miR-28-5p expression in colorectal adenocarcinoma, the most frequent type of colorectal cancer (CRC).

Methods:

Therefore, we isolated total RNA from 182 colorectal adenocarcinoma specimens and 86 paired non-cancerous colorectal mucosae. After polyadenylation of 2 μg total RNA and its reverse transcription using an oligo-dT-adapter primer, we quantified miR-28-5p levels using an in-house-developed reverse-transcription real-time quantitative polymerase chain reaction (RT-qPCR) method, based on the SYBR Green chemistry.

Results:

Comparison of miR-28-5p levels among 86 pairs of colorectal tumors and their adjacent non-cancerous mucosae uncovered the downregulation of miR-28-5p expression in the majority of malignant colorectal tumors. More importantly, high miR-28-5p expression predicts poor disease-free survival (DFS) and overall survival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis revealed that miR-28-5p overexpression is a significant predictor of poor prognosis in colorectal adenocarcinoma, independent of tumor size, histological grade, TNM staging, radiotherapy and chemotherapy. Interestingly, strong miR-28-5p expression retains its predictive potential regarding relapse among patients with negative regional lymph nodes, and predicts poor OS in patients diagnosed with non-metastatic colorectal adenocarcinoma.

Conclusions:

High miR-28-5p expression predicts poor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological prognosticators and standard patient treatment, including radiotherapy and chemotherapy.

This article offers supplementary material which is provided at the end of the article.

Keywords: colon cancer; microRNA-28 (miRNA-28); molecular tumor markers; prognosis; prognostic biomarkers; real-time quantitative real-time PCR (RT-qPCR)

References

  • 1.

    Smith RA, Cokkinides V, Brooks D, Saslow D, Brawley OW. Cancer screening in the United States, 2010: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2010;60:99–119.PubMedCrossrefGoogle Scholar

  • 2.

    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917.CrossrefPubMedGoogle Scholar

  • 3.

    Schoen RE. Families at risk for colorectal cancer: risk assessment and genetic testing. J Clin Gastroenterol 2000;31:114–20.PubMedCrossrefGoogle Scholar

  • 4.

    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67.CrossrefPubMedGoogle Scholar

  • 5.

    Steinberg SM, Barkin JS, Kaplan RS, Stablein DM. Prognostic indicators of colon tumors. The gastrointestinal tumor study group experience. Cancer 1986;57:1866–70.CrossrefGoogle Scholar

  • 6.

    Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 2004;54:295–308.CrossrefPubMedGoogle Scholar

  • 7.

    Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science 2001;294:862–4.CrossrefPubMedGoogle Scholar

  • 8.

    Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 2006;6:259–69.PubMedCrossrefGoogle Scholar

  • 9.

    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6:857–66.CrossrefPubMedGoogle Scholar

  • 10.

    Luo X, Burwinkel B, Tao S, Brenner H. MicroRNA signatures: novel biomarker for colorectal cancer? Cancer Epidemiol Biomarkers Prev 2011;20:1272–86.PubMedCrossrefGoogle Scholar

  • 11.

    Zhao J, Zhang Y, Zhao G. Emerging role of microRNA-21 in colorectal cancer. Cancer Biomark 2015;15:219–26.CrossrefPubMedGoogle Scholar

  • 12.

    Ferraro A, Kontos CK, Boni T, Bantounas I, Siakouli D, Kosmidou V, et al. Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGBeta4-PDCD4) as predictor of metastatic tumor potential. Epigenetics 2014;9:129–41.CrossrefGoogle Scholar

  • 13.

    Su J, Liang H, Yao W, Wang N, Zhang S, Yan X, et al. MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PLoS One 2014;9:e114420.PubMedCrossrefGoogle Scholar

  • 14.

    Almeida MI, Nicoloso MS, Zeng L, Ivan C, Spizzo R, Gafa R, et al. Strand-specific miR-28-5p and miR-28-3p have distinct effects in colorectal cancer cells. Gastroenterology 2012;142:886–96.PubMedCrossrefGoogle Scholar

  • 15.

    Xu J, Jiang N, Shi H, Zhao S, Yao S, Shen H. miR-28-5p promotes the development and progression of ovarian cancer through inhibition of N4BP1. Int J Oncol 2017;50:1383–91.CrossrefGoogle Scholar

  • 16.

    Palakurthy RK, Wajapeyee N, Santra MK, Gazin C, Lin L, Gobeil S, et al. Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression. Mol Cell 2009;36:219–30.CrossrefPubMedGoogle Scholar

  • 17.

    Shi X, Teng F. Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1). Mole Cell Biochem 2015;408:283–93.CrossrefGoogle Scholar

  • 18.

    Hell MP, Thoma CR, Fankhauser N, Christinat Y, Weber TC, Krek W. miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res 2014;74:2432–43.PubMedCrossrefGoogle Scholar

  • 19.

    Wang C, Wu C, Yang Q, Ding M, Zhong J, Zhang CY, et al. miR-28-5p acts as a tumor suppressor in renal cell carcinoma for multiple antitumor effects by targeting RAP1B. Oncotarget 2016;7:73888–902.PubMedGoogle Scholar

  • 20.

    Zhu RY, Zhang D, Zou HD, Zuo XS, Zhou QS, Huang H. MiR-28 inhibits cardiomyocyte survival through suppressing PDK1/Akt/mTOR signaling. In vitro Cellular Develop Biol. Animal 2016;52:1020–5.Google Scholar

  • 21.

    Nagtegaal ID, Quirke P, Schmoll HJ. Has the new TNM classification for colorectal cancer improved care? Nature reviews. Clin Oncol 2011;9:119–23.Google Scholar

  • 22.

    Diamantopoulos MA, Kontos CK, Kerimis D, Papadopoulos IN, Scorilas A. Upregulated miR-16 expression is an independent indicator of relapse and poor overall survival of colorectal adenocarcinoma patients. Clin Chem Lab Med 2017;55:737–47.PubMedGoogle Scholar

  • 23.

    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3:research0034.1–11.Google Scholar

  • 24.

    Christodoulou S, Alexopoulou DK, Kontos CK, Scorilas A, Papadopoulos IN. Kallikrein-related peptidase-6 (KLK6) mRNA expression is an independent prognostic tissue biomarker of poor disease-free and overall survival in colorectal adenocarcinoma. Tumour Biol 2014;35:4673–85.PubMedCrossrefGoogle Scholar

  • 25.

    Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 2004;10:7252–9.PubMedCrossrefGoogle Scholar

  • 26.

    Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, et al. Annual report to the Nation on the status of cancer, 1975–2014, featuring survival. J Natl Cancer Inst 2017;109. doi: 10.1093/jnci/djx030.Google Scholar

  • 27.

    Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21:1350–6.PubMedCrossrefGoogle Scholar

  • 28.

    Mlcochova J, Faltejskova P, Nemecek R, Svoboda M, Slaby O. MicroRNAs targeting EGFR signalling pathway in colorectal cancer. J Cancer Res Clin Oncol 2013;139:1615–24.PubMedCrossrefGoogle Scholar

  • 29.

    Fan C, Lin Y, Mao Y, Huang Z, Liu AY, Ma H, et al. MicroRNA-543 suppresses colorectal cancer growth and metastasis by targeting KRAS, MTA1 and HMGA2. Oncotarget 2016;7:21825–39.PubMedGoogle Scholar

  • 30.

    Yamada N, Noguchi S, Mori T, Naoe T, Maruo K, Akao Y. Tumor-suppressive microRNA-145 targets catenin delta-1 to regulate Wnt/beta-catenin signaling in human colon cancer cells. Cancer Lett 2013;335:332–42.PubMedCrossrefGoogle Scholar

  • 31.

    Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A, et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 2008;68:5795–802.CrossrefPubMedGoogle Scholar

  • 32.

    Ma Y, Li W, Wang H. Roles of miRNA in the initiation and development of colorectal carcinoma. Curr Pharm Des 2013;19:1253–61.PubMedGoogle Scholar

  • 33.

    Ma Q, Wang X, Li Z, Li B, Ma F, Peng L, et al. microRNA-16 represses colorectal cancer cell growth in vitro by regulating the p53/survivin signaling pathway. Oncol Rep 2013;29:1652–8.PubMedCrossrefGoogle Scholar

  • 34.

    Yu Y, Kanwar SS, Patel BB, Oh PS, Nautiyal J, Sarkar FH, et al. MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFbetaR2) in colon cancer cells. Carcinogenesis 2012;33:68–76.PubMedCrossrefGoogle Scholar

  • 35.

    Schetter AJ, Harris CC. Alterations of microRNAs contribute to colon carcinogenesis. Semin Oncol 2011;38:734–42.PubMedCrossrefGoogle Scholar

  • 36.

    Menendez P, Villarejo P, Padilla D, Menendez JM, Rodriguez-Montes JA. Implications of the histological determination of microRNAs in the screening, diagnosis and prognosis of colorectal cancer. J Surg Oncol 2013;108:70–3.CrossrefPubMedGoogle Scholar

  • 37.

    Madhavan D, Cuk K, Burwinkel B, Yang R. Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures. Front Genet 2013;4:116.PubMedGoogle Scholar

  • 38.

    Bartley AN, Yao H, Barkoh BA, Ivan C, Mishra BM, Rashid A, et al. Complex patterns of altered MicroRNA expression during the adenoma-adenocarcinoma sequence for microsatellite-stable colorectal cancer. Clin Cancer Res 2011;17:7283–93.CrossrefPubMedGoogle Scholar

  • 39.

    Wu CW, Ng SS, Dong YJ, Ng SC, Leung WW, Lee CW, et al. Detection of miR-92a and miR-21 in stool samples as potential screening biomarkers for colorectal cancer and polyps. Gut 2012;61:739–45.CrossrefPubMedGoogle Scholar

  • 40.

    Xiao YF, Yong X, Fan YH, Lu MH, Yang SM, Hu CJ. microRNA detection in feces, sputum, pleural effusion and urine: novel tools for cancer screening [Review]. Oncol Rep 2013;30:535–44.PubMedCrossrefGoogle Scholar

  • 41.

    Kalimutho M, Del Vecchio Blanco G, Di Cecilia S, Sileri P, Cretella M, Pallone F, et al. Differential expression of miR-144* as a novel fecal-based diagnostic marker for colorectal cancer. J Gastroenterol 2011;46:1391–402.CrossrefPubMedGoogle Scholar

  • 42.

    Rapti SM, Kontos CK, Papadopoulos IN, Scorilas A. High miR-96 levels in colorectal adenocarcinoma predict poor prognosis, particularly in patients without distant metastasis at the time of initial diagnosis. Tumour Biol 2016;37:11815–24.CrossrefPubMedGoogle Scholar

  • 43.

    Rapti SM, Kontos CK, Papadopoulos IN, Scorilas A. Enhanced miR-182 transcription is a predictor of poor overall survival in colorectal adenocarcinoma patients. Clin Chem Lab Med 2014;52:1217–27.PubMedGoogle Scholar

  • 44.

    Adamopoulos PG, Kontos CK, Rapti SM, Papadopoulos IN, Scorilas A. miR-224 overexpression is a strong and independent prognosticator of short-term relapse and poor overall survival in colorectal adenocarcinoma. Int J Oncol 2015;46:849–59.PubMedCrossrefGoogle Scholar

  • 45.

    Kerimis D, Kontos CK, Christodoulou S, Papadopoulos IN, Scorilas A. Elevated expression of miR-24-3p is a potentially adverse prognostic factor in colorectal adenocarcinoma. Clin Biochem 2017;50:285–92.CrossrefPubMedGoogle Scholar

  • 46.

    Kontos CK, Tsiakanikas P, Avgeris M, Papadopoulos IN, Scorilas A. miR-15a-5p, A novel prognostic biomarker, predicting recurrent colorectal adenocarcinoma. Mol Diagn Ther 2017;21:453–64.CrossrefPubMedGoogle Scholar

  • 47.

    Rapti SM, Kontos CK, Christodoulou S, Papadopoulos IN, Scorilas A. miR-34a overexpression predicts poor prognostic outcome in colorectal adenocarcinoma, independently of clinicopathological factors with established prognostic value. Clin Biochem 2017;50:918–24.CrossrefPubMedGoogle Scholar

  • 48.

    Wang C, Hu J, Lu M, Gu H, Zhou X, Chen X, et al. A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci Rep 2015;5:7610.CrossrefPubMedGoogle Scholar

  • 49.

    Zhou SL, Hu ZQ, Zhou ZJ, Dai Z, Wang Z, Cao Y, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology 2016;63:1560–75.PubMedCrossrefGoogle Scholar

  • 50.

    Lim EL, Trinh DL, Scott DW, Chu A, Krzywinski M, Zhao Y, et al. Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients. Genome Biol 2015;16:18.CrossrefPubMedGoogle Scholar

  • 51.

    Schneider NI, Langner C. Prognostic stratification of colorectal cancer patients: current perspectives. Cancer Manag Res 2014;6:291–300.PubMedGoogle Scholar

  • 52.

    Du WW, Fang L, Li M, Yang X, Liang Y, Peng C, et al. MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling. J Cell Sci 2013;126:1440–53.PubMedCrossrefGoogle Scholar

  • 53.

    Tian R, Liu T, Qiao L, Gao M, Li J. Decreased serum microRNA-206 level predicts unfavorable prognosis in patients with melanoma. Int J Clin Exp Pathol 2015;8:3097–103.PubMedGoogle Scholar

About the article

Received: 2017-05-15

Accepted: 2017-12-17

Published Online: 2018-04-24

Published in Print: 2018-05-24


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 56, Issue 6, Pages 990–1000, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2017-0430.

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