MicroRNA-6826 and -6875 in plasma are valuable non‑invasive biomarkers that predict the efficacy of vaccine treatment against metastatic colorectal cancer

Kijima,Taiki; Hazama,Shoichi; Tsunedomi,Ryouichi; Tanaka,Hironori; Takenouchi,Hiroko; Kanekiyo,Shinsuke; Inoue,Yuka; Nakashima,Masao; Iida,Michihisa; Sakamoto,Kazuhiko; Suzuki,Nobuaki; Takeda,Shigeru; Ueno,Tomio; Yamamoto,Shigeru; Yoshino,Shigefumi; Okuno,Kiyotaka; Nagano,Hiroaki

doi:10.3892/or.2016.5267

MicroRNA-6826 and -6875 in plasma are valuable non‑invasive biomarkers that predict the efficacy of vaccine treatment against metastatic colorectal cancer

Authors:
- Taiki Kijima
- Shoichi Hazama
- Ryouichi Tsunedomi
- Hironori Tanaka
- Hiroko Takenouchi
- Shinsuke Kanekiyo
- Yuka Inoue
- Masao Nakashima
- Michihisa Iida
- Kazuhiko Sakamoto
- Nobuaki Suzuki
- Shigeru Takeda
- Tomio Ueno
- Shigeru Yamamoto
- Shigefumi Yoshino
- Kiyotaka Okuno
- Hiroaki Nagano
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Affiliations: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan, Department of Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
Published online on: November 22, 2016 https://doi.org/10.3892/or.2016.5267
Pages: 23-30
Copyright: © Kijima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Various vaccine treatments against metastatic colorectal cancer have been developed and applied. However, to improve the efficacy of immunotherapy, biomarkers that can predict the effects are needed. It has been reported that various microRNAs (miRNAs) in peripheral blood may be useful as non-invasive biomarkers. In this study, miRNAs influencing the efficacy of vaccine treatment were screened for in a microarray analysis of 13 plasma samples that were obtained from patients prior to vaccine treatment. To validate the screening results, real-time RT-PCR was performed using 93 plasma samples obtained from patients prior to vaccine treatment. Four candidate miRNAs were selected according to the results of the comprehensive analysis of miRNA expression, which were ranked using the Fisher criterion and the absolute value of the log2 ratio in the screening analysis. The validation analysis showed that in the HLA-A*2402‑matched patient group (vaccine-treated group), patients with a high expression of plasma miR-6826 had a poorer prognosis than those with a low expression (P=0.048). In contrast, in the HLA-A*2402-unmatched patient group (control group), there was no difference between the patients with high or low plasma miR-6826 expression (P=0.168). Similar results were obtained in the analysis of miR-6875 (P=0.029 and P=0.754, respectively). Moreover, multivariate analysis of the Cox regression model indicated that the expression of miR-6826 was the most significant predictor for overall survival (P=0.003, hazard ratio, 3.670). In conclusion, plasma miR-6826 and miR-6875 may be predictive biomarkers for a poor response to vaccine treatment. Although further clarification is needed regarding the functions of miR-6826 and miR-6875 and their relationship to immune‑related molecules, plasma miR-6826 and miR-6875 may be useful negative biomarkers for predicting the efficacy of vaccine treatment.

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1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Williet N, Fovet M and Phelip JM: Management of metastatic colorectal cancer. Rev Prat. 65:793–797. 2015.(In French). PubMed/NCBI
3	Ciombor KK, Wu C and Goldberg RM: Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med. 66:83–95. 2015. View Article : Google Scholar : PubMed/NCBI
4	Kibe S, Yutani S, Motoyama S, Nomura T, Tanaka N, Kawahara A, Yamaguchi T, Matsueda S, Komatsu N, Miura M, et al: Phase II study of personalized peptide vaccination for previously treated advanced colorectal cancer. Cancer Immunol Res. 2:1154–1162. 2014. View Article : Google Scholar : PubMed/NCBI
5	Hunyadi J, András C, Szabó I, Szántó J, Szluha K, Sipka S, Kovács P, Kiss A, Szegedi G, Altorjay I, et al: Autologous dendritic cell based adoptive immunotherapy of patients with colorectal cancer-A phase I–II study. Pathol Oncol Res. 20:357–365. 2014. View Article : Google Scholar : PubMed/NCBI
6	Diaz LA Jr and Le DT: PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 373:19792015. View Article : Google Scholar : PubMed/NCBI
7	Copier J, Whelan M and Dalgleish A: Biomarkers for the development of cancer vaccines: current status. Mol Diagn Ther. 10:337–343. 2006. View Article : Google Scholar : PubMed/NCBI
8	Whiteside TL: Immune responses to cancer: Are they potential biomarkers of prognosis? Front Oncol. 3:1072013. View Article : Google Scholar : PubMed/NCBI
9	Lagos-Quintana M, Rauhut R, Lendeckel W and Tuschl T: Identification of novel genes coding for small expressed RNAs. Science. 294:853–858. 2001. View Article : Google Scholar : PubMed/NCBI
10	Lee RC and Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 294:862–864. 2001. View Article : Google Scholar : PubMed/NCBI
11	Facciabene A, Motz GT and Coukos G: T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 72:2162–2171. 2012. View Article : Google Scholar : PubMed/NCBI
12	Ueda R, Kohanbash G, Sasaki K, Fujita M, Zhu X, Kastenhuber ER, McDonald HA, Potter DM, Hamilton RL, Lotze MT, et al: Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci USA. 106:10746–10751. 2009. View Article : Google Scholar : PubMed/NCBI
13	Sonda N, Simonato F, Peranzoni E, Calì B, Bortoluzzi S, Bisognin A, Wang E, Marincola FM, Naldini L, Gentner B, et al: miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis. Immunity. 38:1236–1249. 2013. View Article : Google Scholar : PubMed/NCBI
14	Trifari S, Pipkin ME, Bandukwala HS, Äijö T, Bassein J, Chen R, Martinez GJ and Rao A: MicroRNA-directed program of cytotoxic CD8⁺ T-cell differentiation. Proc Natl Acad Sci USA. 110:18608–18613. 2013. View Article : Google Scholar : PubMed/NCBI
15	Min D, Lv XB, Wang X, Zhang B, Meng W, Yu F and Hu H: Downregulation of miR-302c and miR-520c by 1,25(OH)₂D₃ treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer. 109:723–730. 2013. View Article : Google Scholar : PubMed/NCBI
16	Huang Z, Huang D, Ni S, Peng Z, Sheng W and Du X: Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 127:118–126. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yuan D, Li K, Zhu K, Yan R and Dang C: Plasma miR-183 predicts recurrence and prognosis in patients with colorectal cancer. Cancer Biol Ther. 16:268–275. 2015. View Article : Google Scholar : PubMed/NCBI
18	Hazama S, Nakamura Y, Takenouchi H, Suzuki N, Tsunedomi R, Inoue Y, Tokuhisa Y, Iizuka N, Yoshino S, Takeda K, et al: A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. J Transl Med. 12:632014. View Article : Google Scholar : PubMed/NCBI
19	Hazama S, Nakamura Y, Tanaka H, Hirakawa K, Tahara K, Shimizu R, Ozasa H, Etoh R, Sugiura F, Okuno K, et al: A phase II study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study). J Transl Med. 12:1082014. View Article : Google Scholar : PubMed/NCBI
20	Hazama S, Takenouchi H, Tsunedomi R, Iida M, Suzuki N, Iizuka N, Inoue Y, Sakamoto K, Nakao M, Shindo Y, et al: Predictive biomarkers for the outcome of vaccination of five therapeutic epitope peptides for colorectal cancer. Anticancer Res. 34:4201–4205. 2014.PubMed/NCBI
21	Shindo Y, Hazama S, Nakamura Y, Inoue Y, Kanekiyo S, Suzuki N, Takenouchi H, Tsunedomi R, Nakajima M, Ueno T, et al: miR-196b, miR-378a and miR-486 are predictive biomarkers for the efficacy of vaccine treatment in colorectal cancer. Oncol Lett. (In Press).
22	Uchida N, Tsunoda T, Wada S, Furukawa Y, Nakamura Y and Tahara H: Ring finger protein 43 as a new target for cancer immunotherapy. Clin Cancer Res. 10:8577–8586. 2004. View Article : Google Scholar : PubMed/NCBI
23	Shimokawa T, Matsushima S, Tsunoda T, Tahara H, Nakamura Y and Furukawa Y: Identification of TOMM34, which shows elevated expression in the majority of human colon cancers, as a novel drug target. Int J Oncol. 29:381–386. 2006.PubMed/NCBI
24	Suda T, Tsunoda T, Daigo Y, Nakamura Y and Tahara H: Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci. 98:1803–1808. 2007. View Article : Google Scholar : PubMed/NCBI
25	Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M and Tahara H: Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 12:5841–5849. 2006. View Article : Google Scholar : PubMed/NCBI
26	Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M and Tahara H: Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 65:4939–4946. 2005. View Article : Google Scholar : PubMed/NCBI
27	Smyth GK: limma: Linear models for microarray dataBioinformatics and Computational Biology Solutions Using R and Bioconductor: Statistics for Biology and Health. Gentleman R, Carey V, Dudoit S, Irizarry R and Huber W: Springer; New York: pp. 397–420. 2005, View Article : Google Scholar
28	Hu Z, Dong J, Wang LE, Ma H, Liu J, Zhao Y, Tang J, Chen X, Dai J, Wei Q, et al: Serum microRNA profiling and breast cancer risk: the use of miR-484/191 as endogenous controls. Carcinogenesis. 33:828–834. 2012. View Article : Google Scholar : PubMed/NCBI
29	Zheng G, Wang H, Zhang X, Yang Y, Wang L, Du L, Li W, Li J, Qu A, Liu Y, et al: Identification and validation of reference genes for qPCR detection of serum microRNAs in colorectal adenocarcinoma patients. PLoS One. 8:e830252013. View Article : Google Scholar : PubMed/NCBI
30	Boon T and van der Bruggen P: Human tumor antigens recognized by T lymphocytes. J Exp Med. 183:725–729. 1996. View Article : Google Scholar : PubMed/NCBI
31	Kojima M, Sudo H, Kawauchi J, Takizawa S, Kondou S, Nobumasa H and Ochiai A: MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers. PLoS One. 10:e01182202015. View Article : Google Scholar : PubMed/NCBI
32	Shimomura A, Shiino S, Kawauchi J, Takizawa S, Sakamoto H, Matsuzaki J, Ono M, Takeshita F, Niida S, Shimizu C, et al: Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Sci. 107:326–334. 2016. View Article : Google Scholar : PubMed/NCBI
33	Chen S, Wang L, Fan J, Ye C, Dominguez D, Zhang Y, Curiel TJ, Fang D, Kuzel TM and Zhang B: Host miR155 promotes tumor growth through a myeloid-derived suppressor cell-dependent mechanism. Cancer Res. 75:519–531. 2015. View Article : Google Scholar : PubMed/NCBI
34	Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA and Rudensky AY: Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 445:936–940. 2007. View Article : Google Scholar : PubMed/NCBI
35	Gajewski TF, Schreiber H and Fu YX: Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 14:1014–1022. 2013. View Article : Google Scholar : PubMed/NCBI
36	Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, et al: Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 9:1477–1483. 2003. View Article : Google Scholar : PubMed/NCBI
37	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI