Multi-drug resistance (MDR) is one of the main obstacles for treatment of advanced/recurrent hepatocellular carcinoma (HCC). We have previously identified arsenic trioxide (ATO) as an effective metastasis/angiogenesis inhibitor in HCC. Here, we further found that MDR-HCC cells were more sensitive to ATO. The MDR-HCC cells were used as experimental models. Biological functions were investigated using cell transfection, polymerase chain reaction, western blot, southwestern blot, immunostaining, immunoprecipitation plus atomic fluorescence spectrometry, and so on. The MDR-HCC cells underwent high oxidative stress condition, and employed adaptive mechanisms for them to survive; while ATO abolished such mechanisms via targeting the 14–3-3η/nuclear factor kappa B (NF-κB) feedback Loop. Briefly, in MDR cells, the increase of ROS activated NF-κB signaling, which transcriptionally activated 14–3-3η. Meanwhile, the activation of NF-κB can be constitutively maintained by 14–3-3η. As a NF-κB inhibitor, ATO transcriptionally inhibited the 14–3-3η mRNA level. Meanwhile, ATO was also validated to directly bind to 14–3-3η, enhancing the degradation of 14–3-3η protein in an ubiquitination-dependent manner. Knockdown of 14–3-3η reduced the ATO-induced reversal extents of drug resistance in MDR cells. 14–3-3η/NF-κB feedback loop plays an important role in maintaining the MDR phenotype in HCC. Moreover, via targeting such feedback loop, ATO could be considered as a potential molecular targeted agent for the treatment of HCC.

MicroRNA-206 attenuates the growth and angiogenesis in non-small cell lung cancer cells by blocking the 14-3-3/STAT3/HIF-1/VEGF signaling

Glabridin (GLA), a major component extracted from licorice root, has anti-inflammatory and antioxidant activities, but few studies report its mechanism of inhibition of angiogenesis. This study was an extension of our previous work, which demonstrated that GLA suppressed angiogenesis in human breast cancer (MDA-MB-231 and Hs-578T) cells. Breast cancer is one of the most common malignant diseases in females worldwide, and the major cause of mortality is metastasis that is primarily attributed to angiogenesis. Thus, anti-angiogenesis has become a strategy for the treatment of breast cancer. Cell viability of different concentration treatment groups were detected by Cell Counting Kit-8 assay. The expression of several related genes in the Wnt1 signaling pathway in MDA-MB-231 and Hs-578T cells treated with GLA were measured at both the transcription and translation levels using quantitative real-time PCR analyses and western blotting. Immunofluorescence assay analyzed the nuclear translocation of β-catenin. The microRNA-inhibitor was used to knockdown microRNA-148a (miR-148a) expression. Angiogenic potentials of breast cancer cells were analyzed by enzyme-linked immunosorbent assay (ELISA) and tube formation in vitro. GLA attenuated angiogenesis by the suppression of miR-148a-mediated Wnt/β-catenin signaling pathway in two human breast cancer cell lines (MDA-MB-231 and Hs-578T). GLA also upregulated the expression of miR-148a in a dose-dependent manner, miR-148a, which could directly target Wnt-3′-untranslated regions (UTRs), and decreased the expression of Wnt1, leading to β-catenin accumulation in the membranes from the cytoplasm and nucleus. Downregulation of miR-148a contributed to the reduction of GLA-induced suppression of the Wnt/β-catenin signaling pathway, the angiogenesis and vascular endothelial grow factor (VEGF) secretion. Our study identified a molecular mechanism of the GLA inhibition of angiogenesis through the Wnt/β-catenin signaling pathway via miR-148a, suggesting that GLA could serve as an adjuvant chemotherapeutic agent for breast cancer.