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, Yuichi; Nakashima, Mami; Iida, Michihisa; Sakamoto, Kazuhiko; Suzuki, Nobuaki; Takeda, Shigeru; Ueno, Takayoshi; Yamamoto, Shigeru; Yoshino, Shigefumi; Okuno, Kiyotaka

doi:10.3892/or.2016.5267

Cited by 46 publications

(28 citation statements)

References 38 publications

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“…miR-221, miR-222, miR-659, miR-4470, miR-4669, miR-5703 and RNU6B (internal control)-specific cDNA synthesis was performed using 10 ng of total RNA and TaqMan miRNA primers (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA). RT-qPCR analyses were performed using the following TaqMan miRNA assays: miR-221-3p (ID000524), miR-222-3p (ID002276), miR-659 (ID001514), miR-4470 (ID464583_mat), miR-4669 (ID464125_mat), miR5703 (ID472811_mat) and RNU6B (ID001093) with specific primers (Applied Biosystems; Thermo Fisher Scientific, Inc.) as previously described (14). In brief, cDNA was synthesized from total RNA (10 ng) in a 7.5-µl reaction volume (RT primer 1.5 µl, total RNA lysate 2.5 µl, RT mix 3.5 µl) using the TaqMan ® MicroRNA Reverse Transcription kit.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

et al. 2018

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The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT‑qPCR analysis of the stroma showed that the expression levels of miR‑221 and miR‑222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT‑qPCR analysis of 101 CRC samples showed that a high expression level of miR‑221 or miR‑222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR‑221 and miR‑222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC.

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Section: Methodsmentioning

confidence: 99%

Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

et al. 2018

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“…In another example, miR‐20b, ‐21 and ‐130b are upregulated in advanced CRC and inhibit PTEN expression, resulting in PD‐L1 overexpression . In addition, some miRNAs have been mentioned as possible biomarkers for immunotherapy …”

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confidence: 99%

“…(17) In addition, some miRNAs have been mentioned as possible biomarkers for immunotherapy. (18)(19)(20) Cancer tissues consist of cancer cells and surrounding stromal cells, including inflammatory cells, immunocompetent cells, endothelial cells, and fibroblasts. Stromal cells in the tumor microenvironment play an important role in cancer metastasis.…”

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miR‐125b‐1 and miR‐378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer

et al. 2017

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Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse‐transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR‐125b‐1 in cancer cells (P = 0.040), and miR‐378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR‐378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027–7.585; P = 0.044). In conclusion, miR‐125b‐1 and miR‐378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer.

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“…Although CEA, CA19-9 and CRP are included as predictive and prognostic biomarkers in CRC (14-16), they are not necessarily adapted to immunotherapy. To this purpose, we have previously reported candidate biomarkers of efficacy for such peptide-vaccine treatments (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

IgG response to MHC class I epitope peptides is a quantitative predictive biomarker in the early course of treatment of colorectal cancer using therapeutic peptides

et al. 2018

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Cancer vaccines have been developed as a new therapeutic approach, however, their clinical benefit remains limited. We previously performed a phase II study for advanced colorectal cancer (CRC) using five human leukocyte antigen (HLA-A*24:02)-restricted peptides derived from kinase of the outer chloroplast membrane 1, translocase of outer mitochondrial membrane 34 (TOMM34), ring finger protein 43 (RNF43), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2. In the present study the relationship between overall survival (OS) and several biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to these five peptides, was investigated. In 89 advanced CRC patients treated with a combination therapy consisting of these five peptides and oxaliplatin-based chemotherapy, plasma was collected before and after 3 months of vaccine administration. IgGs reactive to each of the five peptides were assessed using the multiplex bead suspension Luminex system. Antigen-specific T-cell responses were estimated by enzyme-linked immunoSpot assay. Plasma levels of TOMM34 IgG (P<0.001), RNF43 IgG (P<0.001) and VEGFR2 IgG (P<0.001) were significantly increased after vaccination and stronger VEGFR2 IgG responses correlated significantly with OS in HLA-matched patients (P=0.034). CTL responses to VEGFR1 and VEGFR2 were also significantly increased in the HLA-matched group (P=0.049 and P<0.001, respectively). However, increased CTL response did not correlate with OS. Multivariate analysis indicated that IgG responses to VEGFR2 were the most significant predictor for OS in the HLA-A*24:02-matched group (P=0.04). Our findings indicated that VEGFR2 IgG responses may be an important immunological biomarker in the early course of treatment for CRC patients treated with therapeutic epitope peptides.

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

Cited by 46 publications

References 38 publications

Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

miR‐125b‐1 and miR‐378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer

IgG response to MHC class I epitope peptides is a quantitative predictive biomarker in the early course of treatment of colorectal cancer using therapeutic peptides

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