microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11

Abstract

BackgroundMost 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.MethodsIn 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.ResultsHerein, 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.ConclusionsThus, 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.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0746-0) contains supplementary material, which is available to authorized users.

STAT3-mediated TH17 cell Differentiation was Related to the Carcinogenesis of Colitis Related Cancer

“…Also, retinoic orphan receptor-γ (RORγ) and signal transducer and activator of transcription 3 (STAT3)are the transcription factors responsible for Th17 differentiation andstabilization.Gerogios et al demonstrated that miR-124 could promote the children UC and pathogenesis by regulating the expression and phosphorylation of STAT3, but special cell type was not involved [14]. The previous study also demonstrated that miR-124 depression was related to carcinogenesis, and development by targeting different gene [23,24,25].These observations suggested that miR-124 played an key role in colitis and sporadic colon cancer.In our present study, we focused on the miR-124 function in Th17 cell and found that miR-124 could inhibit the polarization of Th17 cell and promote the transition of Th17 to treg in colitis and colitis related colon cancer by targeting stat3 gene.These results are consistent with downregulation of miR-124 developingintestinal failure with M1 macrophage phenotype by targeting stat3 and acetylcholinesterase (AChE). We believe that in the absence of miR-124 signaling cascade, the presence of intestinal commensal bacteria will drive intestinal CD4 + T helper cells toward Th17 cell polarization, resulting in a hyper-in ammatory response with associated tissue damage and pathogenesis.…”

Peer Review #2 of "Comprehensive analysis of lncRNA-associated competing endogenous RNA network in tongue squamous cell carcinoma (v0.2)"

“…Thus, we speculate that SFTA1P may act as an oncogene. Our ceRNA network indicated that SFTA1P up-regulated the expressions of IL-11 or HOXC8 by binding mir-211, and elevated IL-11 or HOXC8 contributes to development of cancer , such as breast cancer (Cai et al 2018;Li et al 2014) and non-small cell lung cancer (Liu et al 2018;Zhao et al 2018b).…”

microRNAs in the Antitumor Immune Response and in Bone Metastasis of Breast Cancer: From Biological Mechanisms to Therapeutics

“…Similarly, the reduced expression of miR-124 in metastatic bone tissue from breast cancer is associated with aggressive clinical characteristics accompanied with shorter bone metastasis-free survival and OS. Restoration of miR-124 in breast cancer cells resulted in the suppression of bone metastasis in vivo through the targeting of intrleukin-11 (IL-11) and the consequent inhibition of osteoclast progenitor cells differentiation and survival [83].…”