VIM­AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2­mediated HMGCS1 mRNA stabilization.

VIM­AS1, a cancer­specific long non­coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM­AS1 in the proliferation and resistance to anti­androgen therapy of LNCaP and C4­2 prostate cancer cells remains to be determined. In the current study, gain­and­loss experiments were used to investigate the effects of VIM­AS on the proliferation and anti­androgen therapy of LNCaP and C4­2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM­AS1 driving prostate progression. It was demonstrated that VIM­AS1 was upregulated in C4­2 cells, an established castration­resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone­sensitive prostate cancer cell line. The present study further demonstrated that VIM­AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM­AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM­AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4­2 cells in vitro and in vivo. Mechanistically, 3­hydroxy­3­methylglutaryl­CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM­AS1, and VIM­AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM­AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA­protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM­AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM­AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM­AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.

Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the ß-catenin signaling pathway through direct phosphorylation of GSK-3ß at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3ß axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer.

Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.

[Enhanced Degradation of Aniline by PS Oxidation in the Presence of UV and Ferric Oxalate].

Oxidative degradation of aniline by Sodium Persulfate (PS) activated with UV-ferric oxalate[UV-Fe(C2O4)33-] was studied. The effects of Fe(C2O4)33- concentration, PS concentration, and pH on PS activation and aniline degradation were investigated. Results showed that Fe(C2O4)33- concentration and pH determined the reduction process of Fe3+ into Fe2+, which had significant effects on the oxidative degradation of aniline by PS. With an increase in Fe(C2O4)33- concentration, PS decomposition increased; however, when concentrations were>0.75 mmol·L-1, aniline degradation efficiency decreased due to competition with oxalate ions (C2O42-) for SO4·-. Aniline degradation efficiency in processes with different initial Fe(C2O4)33- concentrations followed the sequence:5 mmol·L-1 < 0.25 mmol·L-1 < 0.5 mmol·L-1 < 1 mmol·L-1 < 0.75 mmol·L-1. Neutral and alkaline conditions were not conducive to Fe2+ formation via photochemical reaction. However, with initial pH values of 7 and 9, PS activation efficiency reached 74% and 67% respectively after 300 min due to pH decline during the reaction; aniline removal efficiency was as high as 91% and 97%, respectively, higher than under initial acidic conditions. Furthermore, increased PS concentration was conducive to improvement of aniline degradation efficiency, but when PS concentration was>10 mmol·L-1, the aniline degradation process followed the pseudo first-order reaction kinetics model instead of the second-order reaction kinetics model. PS efficiency for aniline degradation decreased significantly due to the reaction between excessive PS and sulfate radicals.

CD4+T cell specific B7-H1 selectively inhibits proliferation of naïve T cells and Th17 differentiation in experimental autoimmune encephalomyelitis.

It is widely acknowledged that interleukin 17-producing T helper (Th17) cells are critically participant in the pathogenesis of multiple sclerosis. In the current study, we identified that the expression of CD4+T cells specific co-inhibitory molecule B7-homologue 1(B7-H1) in spleenocytes and mononuclear cells isolated from brains and spinal cord were positive correlated with Th1 and Th17 cells generation and disease severity in experimental autoimmune encephalomyelitis (EAE). Furthermore, B7-H1 transgenic mice developed milder EAE symptoms and fewer Th17 cells than B7-H1 wild type mice. We also found the proliferation of naïve CD4+CD62+T cells isolated from B7-H1 transgenic mice was inhibited. And naïve T cells isolated from B7-H1 transgenic mice produced fewer Th17 cells than WT mice in Th17-polarizing conditions, but the Th1, Th2, and inducible Treg differentiation were the similar in naïve T cells isolated from B7-H1 transgenic mice and WT mice. In conclusion, our study show CD4+T cells specific B7-H1 is a slective inhibitor in proliferation of naïve T cells, Th17 differentiation and pathogenesis of multiple sclerosis.

[Microclimate dynamics of pit and mound complex within different sizes of forest gaps in Pinus koraiensis-dominated broadleaved mixed forest].

An investigation was conducted in a 2.25 hm2 plot of Pinus koraiensis-dominated broad-leaved mixed forest to study basic characteristics of 7 small gaps, 5 middle gaps, 3 large gaps and 7 closed stands within 38 pit and mound complexes caused by treefall in May 2012. From June to September 2012, the soil temperature, soil water content and relative humidity at five microsites (pit bottom, pit wall, mound top, mound face and undisturbed closed stands) were measured in six sunny days each month. The results showed that among the five microsites in every month, the mound top had the highest soil temperature and the lowest water content and relative humidity, and vice versa for the pit bottom. Mostly, the differences in the above indicators among the five microsites were significant. From June to September, the mean soil temperatures for all microsites at pit and mound complex in the various gaps and closed stands were in the order of large gap>middle gap >small gap>closed stand; but the soil water content ranked differently every month. In June, August and September, the mean relative humidities for all microsites in the various gaps and closed stands were in the order of closed stand>small gap>middle gap>large gap. Mostly, the differences in the above indicators between all microsites in the various gaps and closed stand were significant. The mean monthly soil temperature and relative humidity were highest in July, but lowest in September. The maximal mean monthly soil water content occurred in July and the minimal one in September for each microsite except the undisturbed closed stands, where the maximal mean monthly soil water content occurred in July. The variation of the microclimate at the pit and mound complex was mainly influenced by gap size, microsite, and time.