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Colon cancer constitutes a major challenge all over the world, which has the fourth highest incidence and the third mortality rate of all cancers. Although the therapeutic modalities have been improved in recent years, the 5 y survival rate remains low. Oxymatrine is one of the main active compounds extracted from roots of Sophora flavescens and was found with therapeutic effect for colon cancers. Recently, microRNAs have been recognized as a type of diagnostic and prognostic biomarker and are implicated in a variety of biological activities underlying the tumourogenesis and cancer development. This study firstly evaluated the anti-tumor efficacy of oxymatrine in colon cancer via cell viability assay, colony formation assay and quantification of E-cadherin/vimentin as a metric of epithelial-mesenchymal transition. MicroRNA profile was conducted to identify effective microRNAs involved in the pharmacological mechanism of oxymatrine. MicroRNA-21 and microRNA-141 were the most differentially expressed microRNAs, and overexpression of both resulted in mitigation of anti-tumor effect of oxymatrine. Phosphatase and tensin homolog was predicted to be microRNA-21 and microRNA-141, which was validated via luciferase assay. Silencing of phosphatase and tensin homolog increased the level of phosphorylated-protein kinase B and phosphorylated-nuclear factor-kappa B and transfection of microRNA-21 and microRNA-141 antagomir yielded increase of them, suggesting that microRNA-21/phosphatase and tensin homolog/protein kinase B and microRNA-141/phosphatase and tensin homolog/protein kinase B were involved in the pharmacological effect of oxymatrine. [ABSTRACT FROM AUTHOR]

Induction of the antiviral interferon response is initiated upon recognition of viral RNA structures by the RIG-I or Mda-5 DEX(D/H) helicases. A complex signaling cascade then converges at the mitochondrial adapter MAVS, culminating in the activation of the IRF and NF-κB transcription factors and the induction of interferon gene expression. We have previously shown that MAVS recruits IκB kinaseϵ (IKKϵ) but not TBK-1 to the mitochondria following viral infection. Here we map the interaction of MAVS and IKKϵ to the C-terminal region of MAVS and demonstrate that this interaction is ubiquitin dependent. MAVS is ubiquitinated following Sendai virus infection, and K63-linked ubiquitination of lysine 500 (K500) of MAVS mediates recruitment of IKKϵ to the mitochondria. Real-time PCR analysis reveals that a K500R mutant of MAVS increases the mRNA level of several interferon-stimulated genes and correlates with increased NF-κB activation. Thus, recruitment of IKKϵ to the mitochondria upon MAVS K500 ubiquitination plays a modulatory role in the cascade leading to NF-κB activation and expression of inflammatory and antiviral genes. These results provide further support for the differential role of IKKϵ and TBK-1 in the RIG-I/Mda5 pathway. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA in HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression level of the lncRNA ANRIL was elevated in HTLV-1-infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knockdown of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2 and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2 but required the formation of an ANRIL/EZH2/p65 ternary complex. A chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that the ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that the lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1-infected cells, which is thought to be critical for oncogenesis. [ABSTRACT FROM AUTHOR]