Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-κB signaling pathway

Abstract

BackgroundThe primary issue arising from prostate cancer (PCa) is its high prevalence to metastasize to bone, which severely affects the quality of life and survival time of PCa patients. miR-210-3p is a well-documented oncogenic miRNA implicated in various aspects of cancer development, progression and metastasis. However, the clinical significance and biological roles of miR-210-3p in PCa bone metastasis remain obscure.MethodsmiR-210-3p expression was evaluated by real-time PCR in 68 bone metastatic and 81 non-bone metastatic PCa tissues. The biological roles of miR-210-3p in the bone metastasis of PCa were investigated both in vitro by EMT and Transwell assays, and in vivo using a mouse model of left cardiac ventricle inoculation. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to discern and examine the relationship between miR-210-3p and its potential targets. RT-PCR was performed to identify the underlying mechanism of miR-210-3p overexpression in bone metastasis of PCa. Clinical correlation of miR-210-3p with its targets was examined in human PCa and metastatic bone tissues.ResultsmiR-210-3p expression is elevated in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. Overexpression of miR-210-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. Upregulating miR-210-3p enhances, while silencing miR-210-3p represses the EMT, invasion and migration of PCa cells in vitro. Importantly, silencing miR-210-3p significantly inhibits bone metastasis of PC-3 cells in vivo. Our results further demonstrate that miR-210-3p maintains the sustained activation of NF-κB signaling via targeting negative regulators of NF-κB signaling (TNF-α Induced Protein 3 Interacting Protein 1) TNIP1 and (Suppressor Of Cytokine Signaling 1) SOCS1, resulting in EMT, invasion, migration and bone metastasis of PCa cells. Moreover, our results further indicate that recurrent gains (amplification) contribute to miR-210-3p overexpression in a small number of PCa patients. The clinical correlation of miR-210-3p with SOCS1, TNIP1 and NF-κB signaling activity is verified in PCa tissues.ConclusionOur findings unravel a novel mechanism for constitutive activation of NF-κB signaling pathway in the bone metastasis of PCa, supporting a functional and clinical significance of epigenetic events in bone metastasis of PCa.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0688-6) contains supplementary material, which is available to authorized users.

Decreased miR-218–5p Levels as a Serum Biomarker in Bone Metastasis of Prostate Cancer

“…Furthermore, several lines of evidence reported that NF-κB signaling plays a critical role in the bone metastasis of cancers [37, 41]. Park et al [42] found that NF-κB signaling promoted the bone resorption characteristics of osteolytic bone metastasis in breast cancer cells via upregulating granulocyte macrophage-colony stimulating factor expression that promoted osteolytic bone metastasis by stimulating osteoclast development.…”

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

“…EMT is a key step toward cancer metastasis . Wnt, TGF‐β, Notch, NF‐κB, and MAPK/ERK have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process .…”

“…21,22 In this study, a novel lncRNA, lncRNA DRHC, was shown to be EMT is a key step toward cancer metastasis. 26 Wnt, 27 TGF-β, 28,29 Notch, 30,31 NF-κB, 32,33 and MAPK/ERK 34 have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process.…”

SMAD3/SP1 complex‐mediated constitutive active loop between lncRNA PCAT7 and TGF‐β signaling promotes prostate cancer bone metastasis

“…Primers for U6 and miR‐324‐5p were purchased from RiboBio. The specific process of qRT‐PCR was described in our previous study (Ren et al , ). The detailed information of primers is presented in Table .…”

“…All mouse experiments were approved by the Institutional Animal Care and Use Committee of Sun Yat‐sen University and performed as previously described (Ren et al , ). Ten mice were used in every group for animal experiments.…”