miR-615-3p expression level in bone marrow is associated with tumor recurrence in hepatocellular carcinoma

Mukai,Ryota; Tomimaru,Yoshito; Nagano,Hiroaki; Eguchi,Hidetoshi; Mimori,Koshi; Tomokuni,Akira; Asaoka,Tadafumi; Wada,Hiroshi; Kawamoto,Koichi; Marubashi,Shigeru; Doki,Yuichiro; Mori,Masaki

doi:10.3892/mco.2015.514

miR-615-3p expression level in bone marrow is associated with tumor recurrence in hepatocellular carcinoma

Authors:
- Ryota Mukai
- Yoshito Tomimaru
- Hiroaki Nagano
- Hidetoshi Eguchi
- Koshi Mimori
- Akira Tomokuni
- Tadafumi Asaoka
- Hiroshi Wada
- Koichi Kawamoto
- Shigeru Marubashi
- Yuichiro Doki
- Masaki Mori
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Affiliations: Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan, Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874‑0838, Japan
Published online on: February 25, 2015 https://doi.org/10.3892/mco.2015.514
Pages: 487-494
Copyright: © Mukai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The significance of disseminated tumor cells (DTCs) in bone marrow (BM) on tumor recurrence has not been investigated in patients with hepatocellular carcinoma (HCC). The aim of the present study was to clarify the molecular characteristics of DTCs that affect postoperative recurrence based on microRNA (miRNA) expression profiles in clinical HCC patients undergoing curative resection. DTCs were prospectively collected from the BM of preoperative HCC patients using immunomagnetic beads and subjected to miRNA microarray analysis. Microarray analysis of nine HCC patients (n=5 patients with postoperative HCC recurrence, n=4 patients without HCC recurrence) demonstrated that miR‑615‑3p is significantly upregulated in the DTCs of patients with recurrence compared to the DTCs from patients without recurrence. In vitro experiments demonstrated that the miR‑615‑3p expression level is significantly correlated with malignant characteristics in HCC cells. These data suggest that miR‑615‑3p in DTCs may play an important role in postoperative HCC recurrence, which suggests that miR‑615‑3p is a potential target molecule for regulating postoperative HCC recurrence.

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1	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
2	Schutte K, Bornschein J and Malfertheiner P: Hepatocellular carcinoma – epidemiological trends and risk factors. Dig Dis. 27:80–92. 2009. View Article : Google Scholar : PubMed/NCBI
3	Zhu AX: Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist. 11:790–800. 2006. View Article : Google Scholar : PubMed/NCBI
4	Braun S, Vogl FD, Naume B, et al: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 353:793–802. 2005. View Article : Google Scholar : PubMed/NCBI
5	Pantel K, Izbicki J, Passlick B, et al: Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet. 347:649–653. 1996. View Article : Google Scholar : PubMed/NCBI
6	Natsugoe S, Nakashima S, Nakajo A, et al: Bone marrow micrometastasis detected by RT-PCR in esophageal squamous cell carcinoma. Oncol Rep. 10:1879–1883. 2003.PubMed/NCBI
7	Oki E, Kakeji Y, Baba H, et al: Clinical significance of cytokeratin positive cells in bone marrow of gastric cancer patients. J Cancer Res Clin Oncol. 133:995–1000. 2007. View Article : Google Scholar : PubMed/NCBI
8	Mimori K, Fukagawa T, Kosaka Y, et al: Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Clin Cancer Res. 14:2609–2616. 2008. View Article : Google Scholar : PubMed/NCBI
9	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
10	Calin GA and Croce CM: MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 66:7390–7394. 2006. View Article : Google Scholar : PubMed/NCBI
11	Hoshino I and Matsubara H: MicroRNAs in cancer diagnosis and therapy: from bench to bedside. Surg Today. 43:467–478. 2013. View Article : Google Scholar : PubMed/NCBI
12	Yang P, Li QJ, Feng Y, et al: TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 22:291–303. 2012. View Article : Google Scholar : PubMed/NCBI
13	Tomokuni A, Eguchi H, Tomimaru Y, et al: miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 414:675–680. 2011. View Article : Google Scholar : PubMed/NCBI
14	Tomimaru Y, Eguchi H, Nagano H, et al: Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol. 56:167–175. 2012. View Article : Google Scholar : PubMed/NCBI
15	Tomimaru Y, Eguchi H, Nagano H, et al: MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 103:1617–1626. 2010. View Article : Google Scholar : PubMed/NCBI
16	Takeyama H, Yamamoto H, Yamashita S, et al: Decreased miR-340 expression in bone marrow is associated with liver metastasis of colorectal cancer. Mol Cancer Ther. 13:976–985. 2014. View Article : Google Scholar : PubMed/NCBI
17	Morimoto O, Nagano H, Miyamoto A, et al: Association between recurrence of hepatocellular carcinoma and α-fetoprotein messenger RNA levels in peripheral blood. Surg Today. 35:1033–1041. 2005. View Article : Google Scholar : PubMed/NCBI
18	Akiyoshi S, Fukagawa T, Ueo H, et al: Clinical significance of miR-144-ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases. Br J Cancer. 107:1345–1353. 2012. View Article : Google Scholar : PubMed/NCBI
19	Yang MH, Chen CL, Chau GY, et al: Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 50:1464–1474. 2009. View Article : Google Scholar : PubMed/NCBI
20	Schmittgen TD, Jiang J, Liu Q and Yang L: A high-throughput method to monitor the expression of microRNA precursors. Nucleic Acids Res. 32:e432004. View Article : Google Scholar : PubMed/NCBI
21	Mori M, Mimori K, Inoue H, et al: Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res. 55:3417–3420. 1995.PubMed/NCBI
22	Yamamoto T, Nagano H, Sakon M, et al: Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-α/5-fluorouracil against Hepatocellular Carcinoma. Clin Cancer Res. 10:7884–7895. 2004. View Article : Google Scholar : PubMed/NCBI
23	Eguchi H, Nagano H, Yamamoto H, et al: Augmentation of antitumor activity of 5-fluorouracil by interferon α is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res. 6:2881–2890. 2000.PubMed/NCBI
24	Sakon M, Umeshita K, Nagano H, et al: Clinical significance of hepatic resection in hepatocellular carcinoma: analysis by disease-free survival curves. Arch Surg. 135:1456–1459. 2000. View Article : Google Scholar : PubMed/NCBI
25	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
26	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
27	Mani SA, Guo W, Liao MJ, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
28	Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R and Kasimir-Bauer S: Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 11:R462009. View Article : Google Scholar : PubMed/NCBI
29	Raimondi C, Gradilone A, Naso G, et al: Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 130:449–455. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kamiyama T, Takahashi M, Nakagawa T, et al: AFP mRNA detected in bone marrow by real-time quantitative RT-PCR analysis predicts survival and recurrence after curative hepatectomy for hepatocellular carcinoma. Ann Surg. 244:451–463. 2006.PubMed/NCBI
31	Jiang A, Zhang S, Li Z, et al: miR-615-3p promotes the phagocytic capacity of splenic macrophages by targeting ligand-dependent nuclear receptor corepressor in cirrhosis-related portal hypertension. Exp Biol Med (Maywood). 236:672–680. 2011. View Article : Google Scholar : PubMed/NCBI
32	Goswami RS, Atenafu EG, Xuan Y, et al: MicroRNA signature obtained from the comparison of aggressive with indolent non-Hodgkin lymphomas: potential prognostic value in mantle-cell lymphoma. J Clin Oncol. 31:2903–2911. 2013. View Article : Google Scholar : PubMed/NCBI
33	Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 351:781–791. 2004. View Article : Google Scholar : PubMed/NCBI
34	Fehm T, Muller V, Alix-Panabieres C and Pantel K: Micrometastatic spread in breast cancer: detection, molecular characterization and clinical relevance. Breast Cancer Res. 10 (Suppl 1):S12008. View Article : Google Scholar : PubMed/NCBI
35	Ignatiadis M, Georgoulias V and Mavroudis D: Micrometastatic disease in breast cancer: clinical implications. Eur J Cancer. 44:2726–2736. 2008. View Article : Google Scholar : PubMed/NCBI
36	Kota J, Chivukula RR, O'Donnell KA, et al: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 137:1005–1017. 2009. View Article : Google Scholar : PubMed/NCBI
37	Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al: Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 327:198–201. 2010. View Article : Google Scholar : PubMed/NCBI
38	Soifer HS, Rossi JJ and Saetrom P: MicroRNAs in disease and potential therapeutic applications. Mol Ther. 15:2070–2079. 2007. View Article : Google Scholar : PubMed/NCBI