MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4.

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

Effectiveness of Botulinum Toxin A in Treatment of Hemiplegic Shoulder Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effectiveness of botulinum toxin A (BTX-A) in the treatment of hemiplegic shoulder pain. DATA SOURCES: PubMed, EMBASE, Elsevier, Springer, Cochrane Library, Physiotherapy Evidence Database, CNKI, and VIP were researched from the earliest records to September 1, 2020. STUDY SELECTION: Randomized controlled trials that compared shoulder BTX-A injections vs a control intervention in patients with a history of hemiplegic shoulder pain after stroke were selected. Among the 620 records screened, 9 trials with 301 eligible patients were included. DATA EXTRACTION: Outcome data were pooled according to follow-up intervals (1, 2, 4, and 12 wk). The primary evaluation indices were pain reduction (visual analog scale [VAS] score) and range of motion (ROM) improvement. The second evaluation indices were upper limb functional improvement, spasticity improvement, and incidence of adverse events. Cochrane risk-of-bias was used to assess the methodological quality of studies independently by 2 evaluators. DATA SYNTHESIS: Meta-analysis revealed a statistically significant decrease in the VAS score in the BTX group vs the control group at 1, 4, and 12 weeks postinjection (wk 1: standardized mean difference [SMD], 0.91; 95% confidence interval [CI], 0.27 to 1.54; wk 4: SMD, 1.63; 95% CI, 0.76 to 2.51; wk 12: SMD, 1.96; 95% CI, 1.44 to 2.47). Furthermore, the meta-analysis demonstrated a statistically significant increase in abduction at 1, 4, and 12 weeks postinjection (wk 1: SMD, 3.71; 95% CI, 0 to 7.41; wk 4: SMD, 8.8; 95% CI, 2.22 to 15.37; wk 12: SMD, 19.59; 95% CI, 9.05 to 30.13) and external rotation at 1, 2, 4 weeks postinjection (wk 1: SMD, 5.67; 95% CI, 0.88 to 10.47; wk 2: SMD, 9.62; 95% CI, 5.57 to 13; wk 4: SMD, 6.89; 95% CI, 2.45 to 11.33) in the BTX group. CONCLUSIONS: BTX-A injection provided greater analgesic effects and increased shoulder abduction and external rotation ROM compared with steroid or placebo injection for the treatment of HSP.

KIF15 promotes human glioblastoma progression under the synergistic transactivation of REST and P300.

Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST in vitro and in vivo and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.

Lumbrokinase Extracted from Earthworms Synergizes with Bevacizumab and Chemotherapeutics in Treating Non-Small Cell Lung Cancer by Targeted Inactivation of BPTF/VEGF and NF-κB/COX-2 Signaling.

As a kind of proteolytic enzyme extracted from earthworms, lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the VEGF promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.

Effective degradation of anthraquinones in Folium Sennae with Monascus fermentation for toxicity reduce and efficacy enhancement.

Folium Sennae are widely used around the world, mainly in purging and removal of endogenous active substances, such as anthraquinone and its derivatives. However, the potential toxicity of anthraquinones to the liver, kidney, and intestinal limits the application of Folium Sennae. In this study, we aimed at safe regulation of Folium Sennae to degrade anthraquinones, boosting medicinal properties and reducing toxicity and potency with Monascus fermentation. Monascus strains H1102 for Folium Sennae fermentation were selected as the initial strain which was capable of producing high yields of functional pigment and low yields of hazardous citrinin. The anthraquinone degradation rate reached 41.2%, with 212.2 U mL-1 of the pigment and approximately 0.038 mg L-1 of the citrinin under optimal fermentation conditions followed by response surface streamlining, which met the requirements of reducing toxicity, increasing efficiency of Monascus fermented Folium Sennae. Furthermore, the Monascus/Folium Sennae culture had no observable toxic effect on HK-2 and L-02 cells in vitro and further inhibited cell apoptosis and necrosis. Overall, our results showed that Monascus fermentation could provide an alternative strategy for toxicity reduction of herbal medicines as well as efficacy enhancement.

BPTF inhibition antagonizes colorectal cancer progression by transcriptionally inactivating Cdc25A.

As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to -178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.

Antioxidant Defenses in the Brains of Bats during Hibernation.

Hibernation is a strategy used by some mammals to survive a cold winter. Small hibernating mammals, such as squirrels and hamsters, use species- and tissue-specific antioxidant defenses to cope with oxidative insults during hibernation. Little is known about antioxidant responses and their regulatory mechanisms in hibernating bats. We found that the total level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the brain of each of the two distantly related hibernating bats M. ricketti and R. ferrumequinum at arousal was lower than that at torpid or active state. We also found that the levels of malondialdehyde (product of lipid peroxidation) of the two hibernating species of bats were significantly lower than those of non-hibernating bats R. leschenaultia and C. sphinx. This observation suggests that bats maintain a basal level of ROS/RNS that does no harm to the brain during hibernation. Results of Western blotting showed that hibernating bats expressed higher amounts of antioxidant proteins than non-hibernating bats and that M. ricketti bats upregulated the expression of some enzymes to overcome oxidative stresses, such as superoxide dismutase, glutathione reductase, and catalase. In contrast, R. ferrumequinum bats maintained a relatively high level of superoxide dismutase 2, glutathione reductase, and thioredoxin-2 throughout the three different states of hibernation cycles. The levels of glutathione (GSH) were higher in M. ricketti bats than in R. ferrumequinum bats and were significantly elevated in R. ferrumequinum bats after torpor. These data suggest that M. ricketti bats use mainly antioxidant enzymes and R. ferrumequinum bats rely on both enzymes and low molecular weight antioxidants (e.g., glutathione) to avoid oxidative stresses during arousal. Furthermore, Nrf2 and FOXOs play major roles in the regulation of antioxidant defenses in the brains of bats during hibernation. Our study revealed strategies used by bats against oxidative insults during hibernation.