Abstract
The high mobility group-box 3 (HMGB3) protein belongs to the high mobility group box (HMG-box) subfamily, and recent studies have shown that HMGB3 is an oncogene for leukemia. HMGB3 is also expressed at a high level in the progression phase of breast and gastric cancer (GC). Using bioinformatic analyses, we found that HMGB3 is a potential target for miR-513b. However, the pathophysiological role of miR-513b and its relevance to the growth and development of GC have yet to be investigated. This study focuses on whether miR-513b acts as a tumor suppressor in GC. Compared with non-malignant adjacent tissues samples, qRT-PCR data showed significant downregulation of miR-513b in 74 GC tissue samples (P < 0.01). Furthermore, western blotting revealed that HMGB3 protein was overexpressed in tumor samples relative to matched, non-malignant adjacent tissues. Western blotting and qRT-PCR results showed that high expression of HMGB3 and low expression of miR-513b were both significantly associated with primary tumors, lymph node metastases, and the clinical stage (P < 0.01). MiR-513b was shown to not only inhibit the proliferation and migration of gastric cancer cells (MKN45 and SGC7901) in the CCK-8 and transwell assays, but also to promote cell apoptosis in a flow-cytometric apoptosis assay. In western blot and luciferase assays, HMGB3 was identified as a major target of miR-513b. Moreover, we also found that the expression of HMGB3 lacking in 3′ UTR could abrogate the anti-migration and pro-apoptosis function of miR-513b. These findings suggest the importance of miR-513b targeting of HMGB3 in the regulation of growth, migration and apoptosis of GC, improve our understanding of the mechanisms of GC pathogenesis, and may promote the development of novel targeted therapies.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Vaccari T, Beltrame M, Ferrari S, Bianchi ME. Hmg4, a new member of the Hmg1/2 gene family. Genomics. 1998;49(2):247–52.
Agresti A, Bianchi ME. HMGB proteins and gene expression. Curr Opin Genet Dev. 2003;13(2):170–8.
Stros M. HMGB proteins: interactions with DNA and chromatin. Biochim Biophys Acta. 2010;1799(1–2):101–13.
Nemeth MJ, Kirby MR, Bodine DM. Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation. Proc Natl Acad Sci USA. 2006;103(37):13783–8.
Petit A, Ragu C, Della-Valle V, Mozziconacci MJ, Lafage-Pochitaloff M, Soler G, et al. NUP98-HMGB3: a novel oncogenic fusion. Leukemia. 2010;24:654–8.
Bao G, Qiao Q, Zhao H, He X. Prognostic value of HMGB1 overexpression in resectable gastric adenocarcinomas. World J Surg Oncol. 2010;8:52.
Staal FJ, de Ridder D, Szczepanski T, Schonewille T, van der Linden EC, van Wering ER, et al. Genome-wide expression analysis of paired diagnosis-relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia. 2010;24(3):491–9.
Song N, Liu B, Jian-Ling W, Zhang R-F, Duan L, He W-S, et al. Prognostic value of HMGB3 expression in patients with non-small cell lung cancer. Tumor Biol. 2013;34(5):2599–603.
Gong Y, Cao Y, Song L, Zhou J, Wang C, Wu B. HMGB3 characterization in gastric cancer. Genet Mol Res. 2013;12(4):6032–9.
Elgamal OA, Park JK, Gusev Y, Azevedo- Pouly AC, Jiang J, Roopra A, et al. Tumor suppressive function of mir-205 in breast cancer is linked to HMGB3 regulation. PLoS ONE. 2013;8(10):e76402.
Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death and tumorigenesis. Br J Cancer. 2006;94(6):776–80.
Wan HY, Guo LM, Liu T, Liu M, Li X, Tang H. Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma. Mol Cancer. 2010;9(16):1–10.
Zamore PD, Haley B. Ribo-gnome: the big world of small RNAs. Science. 2005;309(5740):1519–24.
Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006;15(Spec No 1):R17–29.
Roa W, Brunet B, Guo L, Amanie J, Fairchild A, Gabos Z, et al. Identification of a new microRNA expression profile as a potential cancer screening tool. Clin Invest Med. 2010;33(2):E124.
Shah AA, Leidinger P, Backes C, Keller A, Karpinski P, Sasiadek MM, et al. A set of specific miRNAs is connected with murine and human gastric cancer. Gene Chromosome Cancer. 2013;52(3):237–49.
Liu F, Xiong Y, Zhao Y, Tao L, Zhang Z, Zhang H, et al. Identification of aberrant microRNA expression pattern in pediatric gliomas by microarray. Diagn Pathol. 2013;8(158):1–10.
Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol. 2006;12(1):17–20.
David S, Meltzer SJ. Stomach—genetic and epigenetic alterations of preneoplastic and neoplastic lesions. Cancer Biomark. 2010;9(1–6):493–507.
Zhang H, Li Y, Lai M. The microRNA network and tumor metastasis. Oncogene. 2010;29(7):937–48.
Tang D, Loze MT, Zeh HJ, Kang R. The redox protein HMGB1 regulates cell death and survival in cancer treatment. Autophagy. 2010;6(8):1181–3.
Chen J, Xi B, Zhao Y, Yu Y, Zhang J, Wang C. High-mobility group protein B1 (HMGB1) is a novel biomarker for human ovarian cancer. Gynecol Oncol. 2012;126(1):109–17.
Song B, Song WG, Li ZJ, Xu ZF, Wang XW, Wang CX, et al. Effect of HMGB1 silencing on cell proliferation, invasion and apoptosis of MGC-803 gastric cancer cells. Cell Biochem Funct. 2011;30:11–7.
Tang HR, Luo XQ, Xu G, Wang Y, Feng ZJ, Xu H, et al. High mobility group-box 3 overexpression is associated with poor prognosis of resected gastric adenocarcinoma. World J Gastroenterol. 2013;18(48):7319–26.
Moser B, Janik S, Schiefer AI, Müllauer L, Bekos C, Scharrer A, et al. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology. Plos One. 2014;9(4):e94118.
Qin W, Ren Q, Liu T, Huang Y, Wang J. MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1. FEBS Lett. 2013;587(9):1434–9.
Miao LJ, Huang SF, Sun ZT, Gao ZY, Zhang RX, Liu Y, et al. MiR-449c targets c-myc and inhibits NSCLC cell progression. FEBS Lett. 2013;587(9):1359–65.
Li J, Wang Y, Luo J, Fu Z, Ying J, Yu Y, et al. miR-134 inhibits epithelial to mesenchymal transition by targeting FOXM1 in non-small cell lung cancer cells. FEBS Lett. 2012;586(20):3761–5.
Maciotta S, Meregalli M, Cassinelli L, Parolini D, Farini A, Fraro GD, et al. Hmgb3 is regulated by MicroRNA-206 during muscle. PLoS ONE. 2012;7(8):e43464.
Acknowledgments
This study was supported by Luohe Medical College (No.2014-S-LMC22).
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, X., Zhao, G., Wang, F. et al. Upregulation of miR-513b inhibits cell proliferation, migration, and promotes apoptosis by targeting high mobility group-box 3 protein in gastric cancer. Tumor Biol. 35, 11081–11089 (2014). https://doi.org/10.1007/s13277-014-2405-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2405-z