Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells

Authors: Dominique Z. Jones, M. Lee Schmidt, Suman Suman, Katharine R. Hobbing, Shirish S. Barve, Leila Gobejishvili, Guy Brock, Carolyn M. Klinge, Shesh N. Rai, Jong Park, Geoffrey J. Clark, Rajesh Agarwal, LaCreis R. Kidd

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Dysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa).

Methods

Serum-based miRNA profiling involved 15 men diagnosed with non-metastatic (stage I, III) and metastatic (stage IV) PCa and five age-matched disease-free men using miRNA arrays with select targets confirmed by quantitative real-time PCR (qRT-PCR). The effect of miR-186-5p inhibition or ectopic expression on cellular behavior of PCa cells (i.e., PC-3, MDA-PCa-2b, and LNCaP) involved the use bromodeoxyuridine (BrdU) incorporation, invasion, and colony formation assays. Assessment of the impact of miR-186-5p inhibition or overexpression on selected targets entailed microarray analysis, qRT-PCR, and/or western blots. Statistical evaluation used the modified t-test and ANOVA analysis.

Results

MiR-186-5p was upregulated in serum from PCa patients and metastatic PCa cell lines (i.e., PC-3, MDA-PCa-2b, LNCaP) compared to serum from disease-free individuals or a normal prostate epithelial cell line (RWPE1), respectively. Inhibition of miR-186-5p reduced cell proliferation, invasion, and anchorage-independent growth of PC-3 and/or MDA-PCa-2b PCa cells. AKAP12, a tumor suppressor target of miR-186-5p, was upregulated in PC-3 and MDA-PCa-2b cells transfected with a miR-186-5p inhibitor. Conversely, ectopic miR-186-5p expression in HEK 293 T cells decreased AKAP12 expression by 30%. Both pAKT and β-catenin levels were down-regulated in miR-186-5p inhibited PCa cells.

Conclusions

Our findings suggest miR-186-5p plays an oncogenic role in PCa. Inhibition of miR-186-5p reduced PCa cell proliferation and invasion as well as increased AKAP12 expression. Future studies should explore whether miR-186-5p may serve as a candidate prognostic indicator and a therapeutic target for the treatment of aggressive prostate cancer.
Appendix
Available only for authorised users
Literature
1.
Society AC. Cancer facts and figures 2018. In. Atlanta: American Cancer Society; 2018.
2.
Society AC. Cancer treatment and survivorship facts and figures 2016-2017. Altanta: American Cancer Society; 2016.
3.
Pienta KJ, Loberg R. The “emigration, migration, and immigration” of prostate cancer. Clin Prostate Cancer. 2005;4(1):24–30.CrossRefPubMed
4.
Saldanha G, Ghura V, Potter L, Fletcher A. Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation. Br J Dermatol. 2004;151(1):157–64.CrossRefPubMed
5.
Hassanein AM, Glanz SM, Kessler HP, Eskin TA, Liu C. Beta-catenin is expressed aberrantly in tumors expressing shadow cells. Pilomatricoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol. 2003;120(5):732–6.CrossRefPubMed
6.
Tordonato C, Di Fiore PP, Nicassio F. The role of non-coding RNAs in the regulation of stem cells and progenitors in the normal mammary gland and in breast tumors. Front Genet. 2015;6:72.CrossRefPubMedPubMedCentral
7.
Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC. Beta-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer study group brain tumour committee. J Clin Oncol. 2005;23(31):7951–7.CrossRefPubMed
8.
Cha YJ, Lee JH, Han HH, Kim BG, Kang S, Choi YD, Cho NH. MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis. Prostate. 2016;76(10):937–47.CrossRefPubMed
9.
Ren Q, Liang J, Wei J, Basturk O, Wang J, Daniels G, Gellert LL, Li Y, Shen Y, Osman I, et al. Epithelial and stromal expression of miRNAs during prostate cancer progression. Am J Transl Res. 2014;6(4):329–39.PubMedPubMedCentral
10.
Mihelich BL, Maranville JC, Nolley R, Peehl DM, Nonn L. Elevated serum microRNA levels associate with absence of high-grade prostate cancer in a retrospective cohort. PLoS One. 2015;10(4):e0124245.CrossRefPubMedPubMedCentral
11.
12.
Vanacore D, Boccellino M, Rossetti S, Cavaliere C, D'Aniello C, Di Franco R, Romano FJ, Montanari M, La Mantia E, Piscitelli R, et al. Micrornas in prostate cancer: an overview. Oncotarget. 2017;8(30):50240–51.CrossRefPubMedPubMedCentral
13.
Jia W, Wu Y, Zhang Q, Gao G, Zhang C, Xiang Y. Identification of four serum microRNAs from a genome-wide serum microRNA expression profile as potential non-invasive biomarkers for endometrioid endometrial cancer. Oncol Lett. 2013;6(1):261–7.CrossRefPubMedPubMedCentral
14.
Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S, Lam EW. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 2010;70(1):367–77.CrossRefPubMed
15.
Zhou L, Qi X, Potashkin JA, Abdul-Karim FW, Gorodeski GI. MicroRNAs miR-186 and miR-150 down-regulate expression of the pro-apoptotic purinergic P2X7 receptor by activation of instability sites at the 3′-untranslated region of the gene that decrease steady-state levels of the transcript. J Biol Chem. 2008;283(42):28274–86.CrossRefPubMedPubMedCentral
16.
Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, Chen C. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg. 2009;33(4):698–709.CrossRefPubMedPubMedCentral
17.
Zhang ZL, Bai ZH, Wang XB, Bai L, Miao F, Pei HH. miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of Cancer cells. PLoS One. 2015;10(3):e0118814.CrossRefPubMedPubMedCentral
18.
Zhao BS, Liu SG, Wang TY, Ji YH, Qi B, Tao YP, Li HC, Wu XN. Screening of MicroRNA in patients with esophageal Cancer at same tumor node metastasis stage with different prognoses. Asian Pac J Cancer Prev. 2013;14(1):139–43.CrossRefPubMed
19.
Qi M, Huang X, Zhou L, Zhang J. Identification of differentially expressed microRNAs in metastatic melanoma using next-generation sequencing technology. Int J Mol Med. 2014;33(5):1117–21.CrossRefPubMedPubMedCentral
20.
Yang J, Yuan D, Li J, Zheng S, Wang B. miR-186 downregulates protein phosphatase PPM1B in bladder cancer and mediates G1-S phase transition. Tumour Biol. 2016;37(4):4331–41.CrossRefPubMed
21.
Zhu X, Shen H, Yin X, Long L, Xie C, Liu Y, Hui L, Lin X, Fang Y, Cao Y, et al. miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin. Oncogene. 2016;35(3):323–32.CrossRefPubMed
22.
Cai J, Wu J, Zhang H, Fang L, Huang Y, Yang Y, Zhu X, Li R, Li M. miR-186 downregulation correlates with poor survival in lung adenocarcinoma, where it interferes with cell-cycle regulation. Cancer Res. 2013;73(2):756–66.CrossRefPubMed
23.
Li H, Yin C, Zhang B, Sun Y, Shi L, Liu N, Liang S, Lu S, Liu Y, Zhang J, et al. PTTG1 promotes migration and invasion of human non-small cell lung cancer cells and is modulated by miR-186. Carcinogenesis. 2013;34(9):2145–55.CrossRefPubMed
24.
Cui G, Cui M, Li Y, Liang Y, Li W, Guo H, Zhao S. MiR-186 targets ROCK1 to suppress the growth and metastasis of NSCLC cells. Tumour Biol. 2014;35(9):8933–7.CrossRefPubMed
25.
Ye J, Zhang Z, Sun L, Fang Y, Xu X, Zhou G. miR-186 regulates chemo-sensitivity to paclitaxel via targeting MAPT in non-small cell lung cancer (NSCLC). Mol BioSyst. 2016;12(11):3417–24.CrossRefPubMed
26.
Dong Y, Jin X, Sun Z, Zhao Y, Song X. MiR-186 inhibited migration of NSCLC via targeting cdc42 and effecting EMT process. Mol Cells. 2017;40(3):195–201.PubMedPubMedCentral
27.
Wang H, Shen Q, Zhang X, Yang C, Cui S, Sun Y, Wang L, Fan X, Xu S. The long non-coding RNA XIST controls non-small cell lung Cancer proliferation and invasion by modulating miR-186-5p. Cell Physiol Biochem. 2017;41(6):2221–9.CrossRefPubMed
28.
Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, Wallace TA, Liu CG, Volinia S, Calin GA, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 2008;68(15):6162–70.CrossRefPubMedPubMedCentral
29.
Erdmann K, Kaulke K, Thomae C, Huebner D, Sergon M, Froehner M, Wirth MP, Fuessel S. Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs. BMC Cancer. 2014;14:82.CrossRefPubMedPubMedCentral
30.
Hua X, Xiao Y, Pan W, Li M, Huang X, Liao Z, Xian Q, Yu L. miR-186 inhibits cell proliferation of prostate cancer by targeting GOLPH3. Am J Cancer Res. 2016;6(8):1650–60.PubMedPubMedCentral
31.
Zhao X, Wang Y, Deng R, Zhang H, Dou J, Yuan H, Hou G, Du Y, Chen Q, Yu J. miR186 suppresses prostate cancer progression by targeting Twist1. Oncotarget. 2016;7(22):33136–51.PubMedPubMedCentral
32.
Lu S, Wang MS, Chen PJ, Ren Q, Bai P. miRNA-186 inhibits prostate cancer cell proliferation and tumor growth by targeting YY1 and CDK6. Exp Ther Med. 2017;13(6):3309–14.CrossRefPubMedPubMedCentral
33.
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.CrossRefPubMed
34.
Luu HN, Lin HY, Sorensen KD, Ogunwobi OO, Kumar N, Chornokur G, Phelan C, Jones D, Kidd L, Batra J, et al. miRNAs associated with prostate cancer risk and progression. BMC Urol. 2017;17(1):18.CrossRefPubMedPubMedCentral
35.
Smyth GK. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer; 2005.
36.
Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3.CrossRefPubMed
37.
Terzuoli E, Donnini S, Finetti F, Nesi G, Villari D, Hanaka H, Radmark O, Giachetti A, Ziche M. Linking microsomal prostaglandin E Synthase-1/PGE-2 pathway with miR-15a and −186 expression: novel mechanism of VEGF modulation in prostate cancer. Oncotarget. 2016;7(28):44350–64.CrossRefPubMedPubMedCentral
38.
McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, et al. Effects of mutations in Wnt/beta-catenin, hedgehog, notch and PI3K pathways on GSK-3 activity-diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta. 2016;1863(12):2942–76.CrossRefPubMed
39.
Akakura S, Huang C, Nelson PJ, Foster B, Gelman IH. Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia. Cancer Res. 2008;68(13):5096–103.CrossRefPubMedPubMedCentral
40.
Kojima S, Goto Y, Naya Y. The roles of microRNAs in the progression of castration-resistant prostate cancer. J Hum Genet. 2017;62(1):25–31.CrossRefPubMed
41.
Huo D, Clayton WM, Yoshimatsu TF, Chen J, Olopade OI. Identification of a circulating microRNA signature to distinguish recurrence in breast cancer patients. Oncotarget. 2016;7(34):55231–48.CrossRefPubMedPubMedCentral
42.
Ries J, Vairaktaris E, Agaimy A, Kintopp R, Baran C, Neukam FW, Nkenke E. miR-186, miR-3651 and miR-494: potential biomarkers for oral squamous cell carcinoma extracted from whole blood. Oncol Rep. 2014;31(3):1429–36.CrossRefPubMed
43.
Yao K, He L, Gan Y, Zeng Q, Dai Y, Tan J. MiR-186 suppresses the growth and metastasis of bladder cancer by targeting NSBP1. Diagn Pathol. 2015;10:146.CrossRefPubMedPubMedCentral
44.
Liu Z, Zhang G, Yu W, Gao N, Peng J. miR-186 inhibits cell proliferation in multiple myeloma by repressing Jagged1. Biochem Biophys Res Commun. 2016;469(3):692–7.CrossRefPubMed
45.
Honegger A, Schilling D, Bastian S, Sponagel J, Kuryshev V, Sultmann H, Scheffner M, Hoppe-Seyler K, Hoppe-Seyler F. Dependence of intracellular and exosomal microRNAs on viral E6/E7 oncogene expression in HPV-positive tumor cells. PLoS Pathog. 2015;11(3):e1004712.CrossRefPubMedPubMedCentral
46.
He W, Feng J, Zhang Y, Wang Y, Zang W, Zhao G. microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2. Lab Investig. 2016;96(3):317–24.CrossRefPubMed
47.
Cao C, Sun D, Zhang L, Song L. miR-186 affects the proliferation, invasion and migration of human gastric cancer by inhibition of Twist1. Oncotarget. 2016;7(48):79956–63.CrossRefPubMedPubMedCentral
48.
Ruan T, He X, Yu J, Hang Z. MicroRNA-186 targets yes-associated protein 1 to inhibit hippo signaling and tumorigenesis in hepatocellular carcinoma. Oncol Lett. 2016;11(4):2941–5.CrossRefPubMedPubMedCentral
49.
Jiao D, Wu M, Ji L, Liu F, Liu Y. microRNA-186 suppresses cell proliferation and metastasis through targeting Sentrin specific protease 1 in renal cell carcinoma. Oncol Res. 2018;26(2):249–59.CrossRefPubMed
50.
Wang F, Jiang H, Wang S, Chen B. Dual functional MicroRNA-186-5p targets both FGF2 and RelA to suppress tumorigenesis of glioblastoma Multiforme. Cell Mol Neurobiol. 2017;37(8):1433–42.CrossRefPubMed
51.
Islam F, Gopalan V, Vider J, Wahab R, Ebrahimi F, Lu CT, Kasem K, Lam AKY. MicroRNA-186-5p overexpression modulates colon cancer growth by repressing the expression of the FAM134B tumour inhibitor. Exp Cell Res. 2017;357(2):260–70.CrossRefPubMed
52.
Gelman IH. Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev. 2012;31(3–4):493–500.CrossRefPubMedPubMedCentral
53.
Gelman IH. Emerging roles for SSeCKS/Gravin/AKAP12 in the control of cell proliferation, Cancer malignancy, and Barriergenesis. Genes Cancer. 2010;1(11):1147–56.CrossRefPubMedPubMedCentral
54.
Su B, Bu Y, Engelberg D, Gelman IH. SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway. J Biol Chem. 2010;285(7):4578–86.CrossRefPubMed
55.
Xia W, Unger P, Miller L, Nelson J, Gelman IH. The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res. 2001;61(14):5644–51.PubMed
56.
Xia W, Ni J, Zhuang J, Qian L, Wang P, Wang J. MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12. Int J Biochem Cell Biol. 2016;71:1–11.CrossRefPubMed
57.
Goeppert B, Schmezer P, Dutruel C, Oakes C, Renner M, Breinig M, Warth A, Vogel MN, Mittelbronn M, Mehrabi A, et al. Down-regulation of tumor suppressor a kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology. 2010;52(6):2023–33.CrossRefPubMed
58.
Gelman IH, Gao L. SSeCKS/Gravin/AKAP12 metastasis suppressor inhibits podosome formation via RhoA- and Cdc42-dependent pathways. Mol Cancer Res. 2006;4(3):151–8.CrossRefPubMed
59.
Wise HM, Hermida MA, Leslie NR. Prostate cancer, PI3K, PTEN and prognosis. Clin Sci (Lond). 2017;131(3):197–210.CrossRef
60.
Eastman Q, Grosschedl R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol. 1999;11(2):233–40.CrossRefPubMed
61.
Kypta RM, Waxman J. Wnt/beta-catenin signalling in prostate cancer. Nat Rev Urol. 2012;9(8):418–28.CrossRefPubMed
62.
Dulinska-Litewka J, McCubrey JA, Laidler P. Increased Akt signaling resulting from the loss of androgen responsiveness in prostate cancer. Curr Med Chem. 2013;20(1):144–57.CrossRefPubMed
63.
Wu TT, Sikes RA, Cui Q, Thalmann GN, Kao C, Murphy CF, Yang H, Zhau HE, Balian G, Chung LW. Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int J Cancer. 1998;77(6):887–94.CrossRefPubMed
Metadata
Title
Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells
Authors
Dominique Z. Jones
M. Lee Schmidt
Suman Suman
Katharine R. Hobbing
Shirish S. Barve
Leila Gobejishvili
Guy Brock
Carolyn M. Klinge
Shesh N. Rai
Jong Park
Geoffrey J. Clark
Rajesh Agarwal
LaCreis R. Kidd
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4258-0

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Survival after the diagnosis of breast or colorectal cancer in the GAZA Strip from 2005 to 2014

Research article

Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer

Research article

Gynecologic cancer survivor preferences for long-term surveillance

Research article

Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL

Case report

A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2V617F positive polycythemia vera: a case report

Research article

Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/ β-catenin pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits