Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
Labrie F. Hormonal therapy of prostate cancer. Prog Brain Res. 2010;182:321–41.
Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol. 2013;24:1807–12.
Sartor AO, Fitzpatrick JM. Urologists and oncologists: adapting to a new treatment paradigm in castration-resistant prostate cancer (CRPC). BJU Int. 2012;110:328–35.
Sridhar SS, Freedland SJ, Gleave ME, Higano C, Mulders P, Parker C, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur Urol. 2014;65:289–99.
Sturge J, Caley MP, Waxman J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol. 2011;8:357–68.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Adams BD, Kasinski AL, Slack FJ. Aberrant regulation and function of microRNAs in cancer. Curr Biol. 2014;24:R762–776.
Kojima S, Goto Y, Naya Y. The roles of microRNAs in the progression of castration-resistant prostate cancer. J Hum Genet. 2017;62:25–31.
Goto Y, Kurozumi A, Enokida H, Ichikawa T, Seki N. Functional significance of aberrantly expressed microRNAs in prostate cancer. Int J Urol. 2015;22:242–52.
Kurozumi A, Goto Y, Okato A, Ichikawa T, Seki N. Aberrantly expressed microRNAs in bladder cancer and renal cell carcinoma. J Hum Genet. 2017;62:49–56.
Koshizuka K, Hanazawa T, Fukumoto I, Kikkawa N, Okamoto Y, Seki N. The microRNA signatures: aberrantly expressed microRNAs in head and neck squamous cell carcinoma. J Hum Genet. 2017;62:3–13.
Koshizuka K, Hanazawa T, Arai T, Okato A, Kikkawa N, Seki N. Involvement of aberrantly expressed microRNAs in the pathogenesis of head and neck squamous cell carcinoma. Cancer Metastasis Rev. 2017;36:525–45.
Nohata N, Hanazawa T, Kinoshita T, Okamoto Y, Seki N. MicroRNAs function as tumor suppressors or oncogenes: aberrant expression of microRNAs in head and neck squamous cell carcinoma. Auris Nasus Larynx. 2013;40:143–9.
Mizuno K, Mataki H, Arai T, Okato A, Kamikawaji K, Kumamoto T et al. The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. J Hum Genet. 2017;62:671–8.
Fuse M, Kojima S, Enokida H, Chiyomaru T, Yoshino H, Nohata N, et al. Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer. J Hum Genet. 2012;57:691–9.
Goto Y, Kojima S, Nishikawa R, Kurozumi A, Kato M, Enokida H, et al. MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br J Cancer. 2015;113:1055–65.
Goto Y, Kurozumi A, Arai T, Nohata N, Kojima S, Okato A, et al. Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. Br J Cancer. 2017;117:409–20.
Goto Y, Kurozumi A, Nohata N, Kojima S, Matsushita R, Yoshino H, et al. The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma. Oncotarget. 2016;7:59070–86.
Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget. 2017;8:30288–304.
Fukumoto I, Kinoshita T, Hanazawa T, Kikkawa N, Chiyomaru T, Enokida H, et al. Identification of tumour suppressive microRNA-451a in hypopharyngeal squamous cell carcinoma based on microRNA expression signature. Br J Cancer. 2014;111:386–94.
Nishikawa R, Goto Y, Kurozumi A, Matsushita R, Enokida H, Kojima S, et al. MicroRNA-205 inhibits cancer cell migration and invasion via modulation of centromere protein F regulating pathways in prostate cancer. Int J Urol. 2015;22:867–77.
Arai T, Okato A, Kojima S, Idichi T, Koshizuka K, Kurozumi A et al. Regulation of spindle and kinetochore-associated protein 1 by antitumor miR-10a-5p in renal cell carcinoma. Cancer Sci. 2017;108:2088–101.
Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. Peer J Comp Sci. 2016;2:e 67.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
Kato M, Goto Y, Matsushita R, Kurozumi A, Fukumoto I, Nishikawa R, et al. MicroRNA-26a/b directly regulate La-related protein 1 and inhibit cancer cell invasion in prostate cancer. Int J Oncol. 2015;47:710–8.
Kurozumi A, Goto Y, Matsushita R, Fukumoto I, Kato M, Nishikawa R, et al. Tumor-suppressive microRNA-223 inhibits cancer cell migration and invasion by targeting ITGA3/ITGB1 signaling in prostate cancer. Cancer Sci. 2016;107:84–94.
Nishikawa R, Goto Y, Sakamoto S, Chiyomaru T, Enokida H, Kojima S, et al. Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer. Cancer Sci. 2014;105:802–11.
Nishikawa R, Goto Y, Kojima S, Enokida H, Chiyomaru T, Kinoshita T, et al. Tumor-suppressive microRNA-29s inhibit cancer cell migration and invasion via targeting LAMC1 in prostate cancer. Int J Oncol. 2014;45:401–10.
Okato A, Arai T, Kojima S, Koshizuka K, Osako Y, Idichi T, et al. Dual strands of pre-miR150 (miR1505p and miR1503p) act as antitumor miRNAs targeting SPOCK1 in naive and castration-resistant prostate cancer. Int J Oncol. 2017;51:245–56.
Li C, Finkelstein D, Sherr CJ. Arf tumor suppressor and miR-205 regulate cell adhesion and formation of extraembryonic endoderm from pluripotent stem cells. Proc Natl Acad Sci USA. 2013;110:E1112–1121.
Zhang JY, Sun MY, Song NH, Deng ZL, Xue CY, Yang J. Prognostic role of microRNA-205 in multiple human malignant neoplasms: a meta-analysis of 17 studies. BMJ Open. 2015;5:e006244.
Tucci P, Agostini M, Grespi F, Markert EK, Terrinoni A, Vousden KH, et al. Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proc Natl Acad Sci USA. 2012;109:15312–7.
Griffiths K, Morton MS, Nicholson RI. Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol. 1997;32(Suppl 3):24–40.
Hagman Z, Haflidadottir BS, Ceder JA, Larne O, Bjartell A, Lilja H, et al. miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients. Br J Cancer. 2013;108:1668–76.
Yang F, Li R, Hong A, Duan F, Li Y. Generation and characterization of a polyclonal antibody against human high mobility group box 4. Mol Med Rep.. 2013;8:1460–4.
Sun S, Zhang W, Cui Z, Chen Q, Xie P, Zhou C, et al. High mobility group box-1 and its clinical value in breast cancer. Onco Targets Ther. 2015;8:413–9.
Chung HW, Lim JB. High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression. Cancer Sci. 2017;108:1594–601.
Yang GL, Zhang LH, Bo JJ, Huo XJ, Chen HG, Cao M, et al. Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer. J Surg Oncol. 2012;106:57–61.
Sato N, Koinuma J, Fujita M, Hosokawa M, Ito T, Tsuchiya E, et al. Activation of WD repeat and high-mobility group box DNA binding protein 1 in pulmonary and esophageal carcinogenesis. Clin Cancer Res. 2010;16:226–39.
Xia Y, Papalopulu N, Vogt PK, Li J. The oncogenic potential of the high mobility group box protein Sox3. Cancer Res. 2000;60:6303–6.
Tsai FL, Vijayraghavan S, Prinz J, MacAlpine HK, MacAlpine DM, Schwacha A. Mcm2-7 is an active player in the DNA replication checkpoint signaling cascade via proposed modulation of Its DNA Gate. Mol Cell Biol. 2015;35:2131–43.
Kwok HF, Zhang SD, McCrudden CM, Yuen HF, Ting KP, Wen Q, et al. Prognostic significance of minichromosome maintenance proteins in breast cancer. Am J Cancer Res. 2015;5:52–71.
Ren B, Yu G, Tseng GC, Cieply K, Gavel T, Nelson J, et al. MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene. 2006;25:1090–8.
Padmanabhan V, Callas P, Philips G, Trainer TD, Beatty BG. DNA replication regulation protein Mcm7 as a marker of proliferation in prostate cancer. J Clin Pathol. 2004;57:1057–62.
This study was supported by JSPS KAKENHI (grant numbers; 16H05462, 17K16777, 16K20125, 17K11160, and 15K10801).
Conflict of interest
The authors declare no conflict of interest.
Electronic supplementary material
Kaplan-Meier survival curves showing disease-free survival rates for minichromosome maintenance complex component (MCM) family, genes that are downstream from HMGB3
About this article
Cite this article
Yamada, Y., Nishikawa, R., Kato, M. et al. Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis. J Hum Genet 63, 195–205 (2018). https://doi.org/10.1038/s10038-017-0371-1
Down-regulation of SNHG16 alleviates the acute lung injury in sepsis rats through miR-128-3p/HMGB3 axis
BMC Pulmonary Medicine (2021)
Molecular and Cellular Biochemistry (2021)
BMC Cancer (2020)
Establishment of a novel cell cycle-related prognostic signature predicting prognosis in patients with endometrial cancer
Cancer Cell International (2020)
Cell Death & Disease (2020)