MicroRNA-455 regulates migration and invasion of human hepatocellular carcinoma by targeting Runx2

Qin,Le; Zhang,Yu; Lin,Jie; Shentu,Yangping; Xie,Xiaoxiao

doi:10.3892/or.2016.5139

MicroRNA-455 regulates migration and invasion of human hepatocellular carcinoma by targeting Runx2

Authors:
- Le Qin
- Yu Zhang
- Jie Lin
- Yangping Shentu
- Xiaoxiao Xie
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Affiliations: Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Medical Function Center of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Medical Imaging, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: September 30, 2016 https://doi.org/10.3892/or.2016.5139
Pages: 3325-3332

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Abstract

MicroRNA-455 (miR-455) has been considered as a novel cancer-related miRNA and dysregulated expression frequently occurs in various human types of cancer. However, its clinical significance, its biological function and the underlying molecular signaling involved in hepatocellular carcinoma (HCC) remain to be elucidated. In the present study, we found that the expression level of miR-455 was significantly downregulated in both HCC tissues and cell lines. Low expression of miR-455 was significantly associated with poor prognostic features including multiple tumor nodes, high Edmondson‑Steiner grading, advanced tumor-node‑metastasis (TNM) stage and venous infiltration. In addition, our data revealed that miR-455 was a novel prognostic indicator for predicting the 5-year overall and disease-free survival of HCC patients. The gain- and loss-of-function studies revealed that miR-455 significantly suppressed migration and invasion of HCC cells in vitro. miR-455 was inversely correlated with runt-related transcription factor 2 (Runx2) expression in HCC samples. Moreover, we identified that miR-455 inversely regulated Runx2 expression in HCC cells. In this investigation, Runx2 was found to be a direct downstream target of miR-455. Evidently, alteration in Runx2 expression suppressed the effect of miR-455 on HCC cell migration and invasion. In conclusion, our data demonstrated that miR-455 promotes HCC growth by targeting Runx2 and can potentially be regarded as a novel prognostic indicator and valuable therapeutic strategy for HCC.

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1	Mendell JT: MicroRNAs: Critical regulators of development, cellular physiology and malignancy. Cell Cycle. 4:1179–1184. 2005. View Article : Google Scholar : PubMed/NCBI
2	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
3	Szabo G and Bala S: MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 10:542–552. 2013. View Article : Google Scholar : PubMed/NCBI
4	Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
5	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
6	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar : PubMed/NCBI
7	Liu C, Iqbal J, Teruya-Feldstein J, Shen Y, Dabrowska MJ, Dybkaer K, Lim MS, Piva R, Barreca A, Pellegrino E, et al: MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma. Blood. 122:2083–2092. 2013. View Article : Google Scholar : PubMed/NCBI
8	Hummel R, Wang T, Watson DI, Michael MZ, Van der Hoek M, Haier J and Hussey DJ: Chemotherapy-induced modification of microRNA expression in esophageal cancer. Oncol Rep. 26:1011–1017. 2011.PubMed/NCBI
9	Pathak S, Meng WJ, Nandy SK, Ping J, Bisgin A, Helmfors L, Waldmann P and Sun XF: Radiation and SN38 treatments modulate the expression of microRNAs, cytokines and chemokines in colon cancer cells in a p53-directed manner. Oncotarget. 6:44758–44780. 2015.PubMed/NCBI
10	Shoshan E, Mobley AK, Braeuer RR, Kamiya T, Huang L, Vasquez ME, Salameh A, Lee HJ, Kim SJ, Ivan C, et al: Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol. 17:311–321. 2015. View Article : Google Scholar : PubMed/NCBI
11	Hudson J, Duncavage E, Tamburrino A, Salerno P, Xi L, Raffeld M, Moley J and Chernock RD: Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma. Exp Mol Pathol. 95:62–67. 2013. View Article : Google Scholar : PubMed/NCBI
12	Sand M, Skrygan M, Sand D, Georgas D, Hahn SA, Gambichler T, Altmeyer P and Bechara FG: Expression of microRNAs in basal cell carcinoma. Br J Dermatol. 167:847–855. 2012. View Article : Google Scholar : PubMed/NCBI
13	Zhang Z, Hou C, Meng F, Zhao X, Zhang Z, Huang G, Chen W, Fu M and Liao W: MiR-455-3p regulates early chondrogenic differentiation via inhibiting Runx2. FEBS Lett. 589:3671–3678. 2015. View Article : Google Scholar : PubMed/NCBI
14	Boisen MK, Dehlendorff C, Linnemann D, Nielsen BS, Larsen JS, Osterlind K, Nielsen SE, Tarpgaard LS, Qvortrup C, Pfeiffer P, et al: Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line capecitabine and oxaliplatin with or without bevacizumab. PLoS One. 9:e1094302014. View Article : Google Scholar : PubMed/NCBI
15	Bera A, VenkataSubbaRao K, Manoharan MS, Hill P and Freeman JW: A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer. PLoS One. 9:e1063432014. View Article : Google Scholar : PubMed/NCBI
16	Hamilton MP, Rajapakshe K, Hartig SM, Reva B, McLellan MD, Kandoth C, Ding L, Zack TI, Gunaratne PH, Wheeler DA, et al: Identification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif. Nat Commun. 4:27302013. View Article : Google Scholar : PubMed/NCBI
17	Hiroki E, Akahira J, Suzuki F, Nagase S, Ito K, Suzuki T, Sasano H and Yaegashi N: Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas. Cancer Sci. 101:241–249. 2010. View Article : Google Scholar : PubMed/NCBI
18	Li YJ, Ping C, Tang J and Zhang W: MicroRNA-455 suppresses non-small cell lung cancer through targeting ZEB1. Cell Biol Int. 40:621–628. 2016. View Article : Google Scholar : PubMed/NCBI
19	Chai J, Wang S, Han D, Dong W, Xie C and Guo H: MicroRNA-455 inhibits proliferation and invasion of colorectal cancer by targeting RAF proto-oncogene serine/threonine-protein kinase. Tumour Biol. 36:1313–1321. 2015. View Article : Google Scholar : PubMed/NCBI
20	Song G, Gu L, Li J, Tang Z, Liu H, Chen B, Sun X, He B, Pan Y, Wang S, et al: Serum microRNA expression profiling predict response to R-CHOP treatment in diffuse large B cell lymphoma patients. Ann Hematol. 93:1735–1743. 2014. View Article : Google Scholar : PubMed/NCBI
21	Yang H and Wang Y: Five miRNAs considered as molecular targets for predicting neuroglioma. Tumour Biol. 37:1051–1059. 2015. View Article : Google Scholar : PubMed/NCBI
22	Baniwal SK, Khalid O, Gabet Y, Shah RR, Purcell DJ, Mav D, Kohn-Gabet AE, Shi Y, Coetzee GA and Frenkel B: Runx2 transcriptome of prostate cancer cells: Insights into invasiveness and bone metastasis. Mol Cancer. 9:2582010. View Article : Google Scholar : PubMed/NCBI
23	Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, et al: Runx2 association with progression of prostate cancer in patients: Mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 29:811–821. 2010. View Article : Google Scholar : PubMed/NCBI
24	Brusgard JL, Choe M, Chumsri S, Renoud K, MacKerell AD Jr, Sudol M and Passaniti A: RUNX2 and TAZ-dependent signaling pathways regulate soluble E-cadherin levels and tumorsphere formation in breast cancer cells. Oncotarget. 6:28132–28150. 2015. View Article : Google Scholar : PubMed/NCBI
25	Tandon M, Chen Z and Pratap J: Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells. Breast Cancer Res. 16:R162014. View Article : Google Scholar : PubMed/NCBI
26	van der Deen M, Akech J, Wang T, Fitz Gerald TJ, Altieri DC, Languino LR, Lian JB, van Wijnen AJ, Stein JL and Stein GS: The cancer-related Runx2 protein enhances cell growth and responses to androgen and TGFβ in prostate cancer cells. J Cell Biochem. 109:828–837. 2010.PubMed/NCBI
27	Cohen-Solal KA, Boregowda RK and Lasfar A: RUNX2 and the PI3K/AKT axis reciprocal activation as a driving force for tumor progression. Mol Cancer. 14:1372015. View Article : Google Scholar : PubMed/NCBI
28	Niu DF, Kondo T, Nakazawa T, Oishi N, Kawasaki T, Mochizuki K, Yamane T and Katoh R: Transcription factor Runx2 is a regulator of epithelial-mesenchymal transition and invasion in thyroid carcinomas. Lab Invest. 92:1181–1190. 2012. View Article : Google Scholar : PubMed/NCBI
29	Tandon M, Chen Z, Othman AH and Pratap J: Role of Runx2 in IGF-1Rβ/Akt- and AMPK/Erk-dependent growth, survival and sensitivity towards metformin in breast cancer bone metastasis. Oncogene. 35:4730–4740. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wysokinski D, Blasiak J and Pawlowska E: Role of RUNX2 in breast carcinogenesis. Int J Mol Sci. 16:20969–20993. 2015. View Article : Google Scholar : PubMed/NCBI