MicroRNA-124 Inhibits Bone Metastasis of Breast Cancer by Repressing Interleukin-11

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2018 Jan 19

PMID 29343249

Citations 71

Authors

Wei-Luo Cai

Wen-Ding Huang

Bo Li

Tian-Rui Chen

Zhen-Xi Li

Cheng-Long Zhao

Heng-Yu Li

Yan-Mei Wu

Wang-Jun Yan

Jian-Ru Xiao

Affiliations

Soon will be listed here.

Abstract

Background: Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.

Methods: In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.

Results: Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.

Conclusions: Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.

Citing Articles

Bone-Targeted Fluoropeptide Nanoparticle Inhibits NF-κB Signaling to Treat Osteosarcoma and Tumor-Induced Bone Destruction.

Li L, Rong G, Gao X, Cheng Y, Sun Z, Cai X Adv Sci (Weinh). 2024; 12(1):e2412014.

PMID: 39501934 PMC: 11714165. DOI: 10.1002/advs.202412014.

Dose prediction for cervical cancer in radiotherapy based on the beam channel generative adversarial network.

Xie H, Tan T, Zhang H, Li Q Heliyon. 2024; 10(18):e37472.

PMID: 39309882 PMC: 11415707. DOI: 10.1016/j.heliyon.2024.e37472.

Mapping the function of MicroRNAs as a critical regulator of tumor-immune cell communication in breast cancer and potential treatment strategies.

Abdul Manap A, Wisham A, Wong F, Ahmad Najmi H, Ng Z, Diba R Front Cell Dev Biol. 2024; 12:1390704.

PMID: 38726321 PMC: 11079208. DOI: 10.3389/fcell.2024.1390704.

A potential function for MicroRNA-124 in normal and pathological bone conditions.

Kolipaka R, Magesh I, Ashok Bharathy M, Karthik S, Saranya I, Selvamurugan N Noncoding RNA Res. 2024; 9(3):687-694.

PMID: 38577015 PMC: 10990750. DOI: 10.1016/j.ncrna.2024.02.018.

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors.

Chen S, Lei J, Mou H, Zhang W, Jin L, Lu S Front Immunol. 2024; 15:1335366.

PMID: 38464516 PMC: 10920345. DOI: 10.3389/fimmu.2024.1335366.

References

Joung Y, Darvin P, Kang D, Sp N, Byun H, Lee C . Methylsulfonylmethane Inhibits RANKL-Induced Osteoclastogenesis in BMMs by Suppressing NF-κB and STAT3 Activities. PLoS One. 2016; 11(7):e0159891. PMC: 4957779. DOI: 10.1371/journal.pone.0159891. View

Aubin J, Bonnelye E . Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporos Int. 2001; 11(11):905-13. DOI: 10.1007/s001980070028. View

Liang Y, Wang Q, Zhou C, Yin Q, He M, Yu X . MiR-124 targets Slug to regulate epithelial-mesenchymal transition and metastasis of breast cancer. Carcinogenesis. 2012; 34(3):713-22. PMC: 3581604. DOI: 10.1093/carcin/bgs383. View

Zhou W, Yin H, Wang T, Liu T, Li Z, Yan W . MiR-126-5p regulates osteolysis formation and stromal cell proliferation in giant cell tumor through inhibition of PTHrP. Bone. 2014; 66:267-76. DOI: 10.1016/j.bone.2014.06.021. View

Hanavadi S, Martin T, Watkins G, Mansel R, Jiang W . Expression of interleukin 11 and its receptor and their prognostic value in human breast cancer. Ann Surg Oncol. 2006; 13(6):802-8. DOI: 10.1245/ASO.2006.05.028. View

. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015; 386(10001):1353-1361. DOI: 10.1016/S0140-6736(15)60908-4. View

Vazquez I, Maicas M, Marcotegui N, Conchillo A, Guruceaga E, Roman-Gomez J . Silencing of hsa-miR-124 by EVI1 in cell lines and patients with acute myeloid leukemia. Proc Natl Acad Sci U S A. 2010; 107(44):E167-8. PMC: 2973895. DOI: 10.1073/pnas.1011540107. View

Li L, Luo J, Wang B, Wang D, Xie X, Yuan L . Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer. 2013; 12:163. PMC: 4029407. DOI: 10.1186/1476-4598-12-163. View

Johnstone C, Chand A, Putoczki T, Ernst M . Emerging roles for IL-11 signaling in cancer development and progression: Focus on breast cancer. Cytokine Growth Factor Rev. 2015; 26(5):489-98. DOI: 10.1016/j.cytogfr.2015.07.015. View

10.

Ng P, Tsui S, Lau C, Wong C, Wong W, Huang L . CCAAT/enhancer binding protein beta is up-regulated in giant cell tumor of bone and regulates RANKL expression. J Cell Biochem. 2010; 110(2):438-46. DOI: 10.1002/jcb.22556. View

11.

Vimalraj S, Miranda P, Ramyakrishna B, Selvamurugan N . Regulation of breast cancer and bone metastasis by microRNAs. Dis Markers. 2013; 35(5):369-87. PMC: 3809754. DOI: 10.1155/2013/451248. View

12.

Zhang F, Wang B, Long H, Yu J, Li F, Hou H . Decreased miR-124-3p Expression Prompted Breast Cancer Cell Progression Mainly by Targeting Beclin-1. Clin Lab. 2016; 62(6):1139-45. DOI: 10.7754/clin.lab.2015.151111. View

13.

McCoy E, Hong H, Pruitt H, Feng X . IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells. BMC Cancer. 2013; 13:16. PMC: 3554506. DOI: 10.1186/1471-2407-13-16. View

14.

Lv X, Jiao Y, Qing Y, Hu H, Cui X, Lin T . miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro. Chin J Cancer. 2011; 30(12):821-30. PMC: 4013330. DOI: 10.5732/cjc.011.10289. View

15.

Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T . Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002; 12(9):735-9. DOI: 10.1016/s0960-9822(02)00809-6. View

16.

Li Z, Kang Y . Emerging therapeutic targets in metastatic progression: A focus on breast cancer. Pharmacol Ther. 2016; 161:79-96. PMC: 4851893. DOI: 10.1016/j.pharmthera.2016.03.003. View

17.

Dong L, Chen L, Wang W, Zhang L . Decreased expression of microRNA-124 is an independent unfavorable prognostic factor for patients with breast cancer. Diagn Pathol. 2015; 10:45. PMC: 4430031. DOI: 10.1186/s13000-015-0257-5. View

18.

Akerblom M, Jakobsson J . MicroRNAs as Neuronal Fate Determinants. Neuroscientist. 2013; 20(3):235-42. DOI: 10.1177/1073858413497265. View

19.

Sonntag K, Woo T, Krichevsky A . Converging miRNA functions in diverse brain disorders: a case for miR-124 and miR-126. Exp Neurol. 2011; 235(2):427-35. PMC: 3335933. DOI: 10.1016/j.expneurol.2011.11.035. View

20.

Ho S, Hunt H, Horton R, Pullen J, Pease L . Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989; 77(1):51-9. DOI: 10.1016/0378-1119(89)90358-2. View