Abstract
BackgroundClinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been widely reported to be involved in the progression and metastasis of several human cancer types. However, the clinical significance and biological roles of miR-141-3p in bone metastasis of PCa are still unclear.MethodsmiR-141-3p expression was examined in 89 non-bone metastatic and 52 bone metastatic PCa tissues by real-time PCR. Statistical analysis was performed to investigate the clinical correlation between miR-141-3p expression levels and clinicopathological characteristics in PCa patients. The biological roles of miR-141-3p in bone metastasis of PCa were evaluated both in vitro and a mouse intracardial model in vivo. Bioinformatics analysis, Western blot, luciferase reporter and miRNA immunoprecipitation assays were performed to explore and examine the relationship between miR-141-3p and its potential targets. Clinical correlation of miR-141-3p with its targets was examined in clinical PCa tissues.ResultsmiR-141-3p expression is reduced in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. Low expression of miR-141-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. Furthermore, upregulating miR-141-3p suppresses the EMT, invasion and migration of PCa cells in vitro. Conversely, silencing miR-141-3p yields an opposite effect. Importantly, upregulating miR-141-3p dramatically reduces bone metastasis of PC-3 cells in vivo. Our results further show that miR-141-3p inhibits the activation of NF-κB signaling via directly targeting tumor necrosis factor receptor-associated factor 5(TRAF5) and 6 (TRAF6), which further suppresses invasion, migration and bone metastasis of PCa cells. The clinical negative correlation of miR-141-3p expression with TRAF5, TRAF6 and NF-κB signaling activity is demonstrated in PCa tissues.ConclusionOur findings unravel a novel mechanism underlying the bone metastasis of PCa, suggesting that miR-141-3p mimics might represent a potential therapeutic avenue for the treatment of PCa bone metastasis.
Highlights
Prostate cancer (PCa) exhibits a high avidity to metastasize to bone. miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been widely reported to be involved in the progression and metastasis of several human cancer types
Our results further demonstrate that ectopic expression of miR-141-3p suppresses activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling via targeting Tumor necrosis factor receptor-associated factor 5 (TRAF5) and Tumor necrosis factor receptorassociated factor 6 (TRAF6), which further inhibits invasion, migration and bone metastasis in prostate cancer (PCa)
Results miR-141-3p is downregulated in bone-metastatic PCa tissues Through analyzing the miRNA sequencing dataset of PCa from The Cancer Genome Atlas (TCGA), we found that miR-141-3p expression was downregulated in bone metastatic PCa tissues compared with that in non-bone metastatic PCa tissues (Fig. 1a), and the percentage of low expression of miR-141-3p was higher in bone metastatic PCa tissues than that in non-bone metastatic PCa tissues (Fig. 1b).We further examined the expression levels of miR-141-3p in our PCa tissues and found that the miR-141-3p expression level in bone metastatic PCa tissues was dramatically decreased compared with that in non-bone metastatic PCa tissues (Fig. 1c), and the percentage of low expression of miR-141-3p was higher in bone metastatic PCa tissues than that in nonbone metastatic PCa tissues (Fig. 1d)
Summary
Prostate cancer (PCa) exhibits a high avidity to metastasize to bone. miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been widely reported to be involved in the progression and metastasis of several human cancer types. Prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Constitutive activation of NF-κB signaling has been reported in numerous human cancers, which promotes the initiation, progression and metastasis of malignancies [8,9,10,11,12]. Several lines of evidence have reported that NF-κB signaling plays a critical role in the bone metastasis of cancers [9, 16, 17]. A study by Chen et al reported that NF-κB signaling activity promoted the development of PCa bone metastasis [19]. The underlying mechanism of constitutive activation of NF-κB signaling in the bone metastasis of PCa needs to be further elucidated
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