MicroRNA-16 sensitizes drug-resistant breast cancer cells to Adriamycin by targeting Wip1 and Bcl-2.

Clinical evidence indicates that drug resistance is a major obstacle in the treatment of breast cancer (BC). Drug resistance results in the disease being uncontrollable, and leads to high mortality rates. The aim of the present study was to investigate the chemosensitizing effect of microRNA (miR)-16 on Adriamycin (ADM)-resistant BC cells and the associated mechanisms. BC tumors from 40 patients were collected and reverse transcription-quantitative PCR was used to examine the expression of miR-16. ADM-sensitive (MCF-7/S) and -resistant (MCF-7/A) BC cell lines were used to determine the expression of miR-16 prior to and following transfection with miR-16 mimics or inhibitor. The effects of increased and decreased miR-16 expression on the chemosensitivity of BC cells to ADM was analyzed using MTT, colony survival and flow cytometry assays. miR-16 was found to regulate wild-type p53-induced phosphatase 1 (Wip1) and Bcl-2 expression, as confirmed by western blotting, immunofluorescence staining and luciferase reporter assays. miR-16 expression in drug-resistant tumor tissues and cells was decreased, compared with that the drug-sensitive equivalents. Overexpression of miR-16 in MCF-7/A was associated with a sharp downregulation of Wip1 and Bcl-2 expression, leading to increased ADM-induced cell apoptosis and sensitization of MCF-7/A cells to ADM treatment. Taken together, the results demonstrate that miR-16 may serve as an effective chemosensitizing target to enhance the effects of chemotherapy in drug-resistant BC cells with high Wip1 and Bcl-2 expression. This provides a novel approach to improving the chemotherapeutic efficacy in drug-resistant BC via regulation of miRs.

miR-17-3p Downregulates Mitochondrial Antioxidant Enzymes and Enhances the Radiosensitivity of Prostate Cancer Cells.

Radioresistance remains to be a major obstacle in the management of patients with advanced prostate cancer (PCa). We have identified a mature miR-17-3p processed from the 3' arm of precursor miR-17, which appeared to be able to inhibit three major antioxidant enzymes located in mitochondria, i.e., manganese superoxide dismutase (MnSOD), glutathione peroxidase 2 (Gpx2), and thioredoxin reductase 2 (TrxR2). Here we show that upregulation of miR-17-3p remarkably sensitized PCa cells to ionizing radiation (IR). Reductions of the three antioxidants led to increasing cellular reactive oxygen species (ROS) accumulation as well as declining mitochondrial respiration. The miR-17-3p-mediated dysfunction of mitochondrial antioxidants apparently sensitizing IR therapy was manifested in vitro and in vivo. Substantially, the miR-17-3p effect on suppression of the antioxidants can be efficiently eliminated or attenuated by transfecting with either an miR-17-3p inhibitor or each of the related antioxidant cDNA expression constructs. Overall, in addition to the insights into the functional assessments for the duplex of miR-17-5p and miR-17-3p, the present study highlights the rigorous evidence that demonstrated suppression of multiple mitochondrial antioxidants by a single microRNA (miRNA), thereby providing a promising approach to improve radiotherapy for advanced PCa by targeting mitochondrial function.

HZ08 suppresses RelB-activated MnSOD expression and enhances Radiosensitivity of prostate Cancer cells.

BACKGROUND: The development of radioresistance is one of main causes for therapeutic failure of prostate cancer (PCa). The present study aims to investigate the function and the related mechanism by which HZ08 sensitizes radiotherapeutic efficiency to treat aggressive PCa cells. METHODS: PCa cells were pretreated with HZ08 (6,7-dimethoxy-1-(3,4-dimethoxy) benzyl-2-(N-n-octyl-N'-cyano) guanyl-1,2,3,4-tetrahydroisoquinoline) and followed by ionizing radiation (IR) treatment. Cytotoxicity in the treated cells was analyzed to assess the radiosensitization capacity of HZ08 by flow cytometry, MTT and colony survival assays. The cellular levels of reactive oxygen species (ROS) and oxygen consumption rates (OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. RelB binding to the NF-κB intronic enhancer region of the human SOD2 gene was determined using a ChIP assay. The levels of phosphorylation of PI3K, Akt and IKKα were quantified and further confirmed using a PI3K inhibitor. Finally, the synergistic effect of HZ08 on radiosensitization of PCa cells was validated using a mouse xenograft tumor model. RESULTS: HZ08 enhanced radiosensitivity of PCa cells through increasing ROS and declining mitochondrial respiration due to suppression of mitochondrial antioxidant enzyme MnSOD. Mechanistically, HZ08 appeared to inhibit PI3K/Akt/IKKα signaling axis, resulting in transcriptional repression of MnSOD expression by preventing RelB nuclear translocation. CONCLUSIONS: HZ08 can serve as a useful radiosensitizing agent to improve radiotherapy for treating aggressive PCa cells with high level of constitutive RelB. The present study suggests a promising approach for enhancing radiotherapeutic efficiency to treat advanced PCa by inhibiting antioxidant defense function.

Exosome-mediated miR-222 transferring: An insight into NF-κB-mediated breast cancer metastasis.

The subtypes of distant-organ metastasis led to treatment failure and poor prognosis are major obstacles in the management of patients with advanced breast cancer (BCa). Emerging evidences demonstrated that exosomes act as mediators for intercellular communication between various types of cells in the local tumor microenvironment. The present study aims to investigate whether BCa-derived exosomes are capable of cell-cell transferring miR-222 for BCa metastatic progression. Results showed that exosomal miR-222 is highly expressed in BCa patients with lymphatic metastasis. Consistently, the elevated levels of exosomal miR-222 are closely correlated with the high aggressivity of BCa cell lines. miR-222 promoting the aggressivity of BCa cells was confirmed in vitro and in vivo. Mechanistically, miR-222 directly targets PDLIM2, a tumor suppressor gene, leading to activation of NF-κB signal pathway. In conclusion, the levels of exosomal miR-222 are correlated with BCa metastatic progression. Exosome-transferred miR-222 promotes migration and invasion of BCa cells. miR-222 contributes to tumorigenicity of BCa cells through down-regulation of PDLIM2 and consequently activating NF-κB.

Discrimination and Geographical Origin Prediction of Cynomorium songaricum Rupr. from Different Growing Areas in China by an Electronic Tongue.

Cynomorium songaricum Rupr. is a well-known and widespread plant in China. It has very high medicinal values in many aspects. The study aimed at discriminating and predicting C. songaricum from major growing areas in China. An electronic tongue was used to analyze C. songaricum based on flavor. Discrimination was achieved by principal component analysis and linear discriminant analysis. Moreover, a prediction model was established, and C. songaricum was classified by geographical origins with 100% degree of accuracy. Therefore, the identification method presented will be helpful for further study of C. songaricum.

MiR-31 inhibits migration and invasion by targeting SATB2 in triple negative breast cancer.

Metastasis is the leading cause of death among breast cancer (BCa) patients and triple negative breast cancer (TNBC) as one of BCa subtypes exhibits the worst survival rate due to its highly aggressive and metastatic behavior. A growing body of research has shown that the dynamic expression of microRNAs (miRNAs) was intimately associated with tumor invasion and metastasis. Recent studies have demonstrated miR-31 as a metastasis-suppressor in breast cancer, but it is still known little about the mechanism of it suppresses metastasis. The special AT-rich sequence-binding protein-2 (SATB2) has been reported to involve in tumor proliferation and invasion, but its function and relationship with miR-31 in breast cancer is still unknown. Here we found that the expression of miR-31 was downregulated in TNBC tissue and cell line. MiR-31 expression was increased after MDA-MB-231 cell was treated by 5-aza-2'-deoxycytidine (5-AZA-CdR), enhance the expression of miR-31 significantly inhibited MDA-MB-231 cell migration and invasion, downregulation of miR-31 expression could promoted MCF-7 cell migration and invasion. The expression of SATB2 was negatively correlated with miR-31 and was upregulated in MCF-7 and MDA-MB-231. Silencing SATB2 expression significantly inhibited MCF-7 and MDA-MB-231 cell proliferation, migration and invasion. Luciferase reporter assays indicated SATB2 is a direct target of miR-31. Taken together, these results suggest miR-31 inhibited TNBC cells migration and invasion through suppressing SATB2 expression.