Regulation and Therapeutic Application of Long non-Coding RNA in Tumor Angiogenesis.

Tumor growth and metastasis rely on angiogenesis. In recent years, long non-coding RNAs have been shown to play an important role in regulating tumor angiogenesis. Here, we review the multidimensional modes and relevant molecular mechanisms of long non-coding RNAs in regulating tumor angiogenesis. In addition, we summarize new strategies for tumor anti-angiogenesis therapies by targeting long non-coding RNAs. The aim of this study is to provide new diagnostic targets and treatment strategies for anti-angiogenic tumor therapy.

Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

LncRNA MIR31HG fosters stemness malignant features of non-small cell lung cancer via H3K4me1- and H3K27Ace-mediated GLI2 expression.

Non-coding RNAs are responsible for oncogenesis and the development of stemness features, including multidrug resistance and metastasis, in various cancers. Expression of lncRNA MIR31HG in lung cancer tissues and peripheral sera of lung cancer patients were remarkably higher than that of healthy individuals and indicated a poor prognosis. Functional analysis showed that MIR31HG fosters stemness-associated malignant features of non-small cell lung cancer cells. Further mechanistic investigation revealed that MIR31HG modulated GLI2 expression via WDR5/MLL3/P300 complex-mediated H3K4me and H3K27Ace modification. In vivo MIR31HG repression with an antisense oligonucleotide attenuated tumor growth and distal organ metastasis, whereas MIR31HG promotion remarkably encouraged cellular invasion in lung and liver tissues. Our data suggested that MIR31HG is a potential diagnostic indicator and druggable therapeutic target to facilitate multiple strategic treatments for lung cancer patients.

N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness.

Despite the advent of precision medicine and immunotherapy, mortality due to lung cancer remains high. The sonic hedgehog (SHH) cascade and its key terminal factor, glioma-associated oncogene homolog 1 (GLI1), play a pivotal role in the stemness and drug resistance of lung cancer. Here, we investigated the molecular mechanism of non-canonical aberrant GLI1 upregulation. The SHH cascade was upregulated in stem spheres and chemo-resistant lung cancer cells and was accountable for drug resistance against multiple chemotherapy regimens. GLI1 and the long non-coding RNA SOX2OT were positively regulated, and the GLI1-SOX2OT loop mediated the proliferation of parental and stem-like lung cancer cells. Further mechanistic investigation revealed that SOX2OT facilitated METTL3/14/IGF2BP2-mediated m6A modification and stabilization of the GLI1 mRNA. Additionally, SOX2OT upregulated METTL3/14/IGF2BP2 by sponging miR-186-5p. Functional analysis corroborated that GLI1 acted as a downstream target of METTL3/14/IGF2BP2, and GLI1 silencing could block the oncogenicity of lung cancer stem-like cells. Pharmacological inhibition of the loop remarkably inhibited the oncogenesis of lung cancer cells in vivo. Compared with paired adjacent normal tissues, lung cancer specimens exhibited consistently upregulated GLI1/SOX2OT/METTL3/14/IGF2BP2. The m6A-modified GLI1-SOX2OT loop may serve as a potential therapeutic target and prognostic predictor for lung cancer therapy and diagnosis in the clinic.

Reversing tumor multidrug resistance with a catalytically active covalent organic framework.

We report here a catalytically active nano covalent organic framework [COF(Fe)] with high drug loading capacity for reversing tumor multidrug resistance (MDR). The Fe catalytic sites in COF(Fe) could convert intracellular overexpressed H2O2 into highly reactive ˙OH to induce oxidation stress and down-regulate MDR protein. Therefore, COF(Fe) could enhance the intracellular drug accumulation to overcome MDR, which was demonstrated both in vitro and in vivo.

ATP-triggered mitochondrial cascade reactions for cancer therapy with nanoscale zeolitic imidazole framework-90.

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.

Covalent Organic Framework-Derived Carbonous Nanoprobes for Cancer Cell Imaging.

Covalent organic frameworks (COFs) have emerged as promising materials for biomedical applications, but their functions remain to be explored and the potential toxicity concerns should be resolved. Herein, it is presented that carbonization significantly enhances the fluorescence quenching efficiency and aqueous stability of nanoscale COFs. The probes prepared by physisorbing dye-labeled nucleic acid recognition sequences onto the carbonized COF nanoparticles (termed C-COF) were employed for cell imaging, which could effectively light up biomarkers (survivin and TK1 mRNA) in living cells. The C-COF has enhanced photothermal conversion capacity, indicating that the probes are also promising candidates for photothermal therapy. The potential toxicity concern from the aromatic rigid building units of COFs was detoured by carbonization. Overall, carbonization is a promising strategy for developing biocompatible and multifunctional COF-derived nanoprobes for biomedical applications. This work may inspire more versatile COF-derived nanoprobes for bioanalysis and nanomedicine.

Ultrathin functionalized covalent organic framework nanosheets for tumor-targeted photodynamic therapy.

We developed a modification-facilitated exfoliation strategy for the one-step preparation of ultrathin 2D functionalized covalent organic framework nanosheets (COF NSs). Hyaluronic acid-functionalized ultrathin porphyrin COF NSs (about 5-8 nm) with enhanced reactive oxygen species (ROS) generation effect were readily prepared for tumor-targeted photodynamic therapy.

A dual-catalytic nanoreactor for synergistic chemodynamic-starvation therapy toward tumor metastasis suppression.

Tumor metastasis is extremely deadly for cancer patients and developing effective treatments for deep metastatic tumors remains a major challenge. In this study, we demonstrated a dual-catalytic nanoreactor for tumor metastasis suppression by synergistic Fenton reaction activated chemodynamic therapy (CDT) and glucose oxidase (GOx) initiated starvation therapy. GOx on the surface of hollow mesoporous silica nanoparticles can catalyze the decomposition of intratumoral glucose to generate gluconic acid and H2O2, while Fe3O4 nanoparticles as a Fenton reaction catalyst can in situ catalyze H2O2 to produce highly toxic hydroxyl radicals (˙OH). The oxygen-carrying perfluorohexane (PFC) in the hole of the hollow structures can alleviate the hypoxic environment and promote dual-catalytic reactions. After being disguised by the cancer cell membrane, the delivery efficiency and biological safety of the nanoreactor were effectively improved. The nanoreactor can realize sequential glucose depletion and ˙OH aggregation, which effectively suppress tumor metastasis with negligible side effects.

Rational Design of a Dual-Layered Metal-Organic Framework Nanostructure for Enhancing the Cell Imaging of Molecular Beacons.

As the most popular nucleic acid probe, molecular beacons (MBs) can selectively light up endogenous RNA targets without specific treatment. However, the poor cell permeability and unsatisfied intracellular stability of MBs significantly restricted their detection performance. Herein, we report the encapsulation of MB within a dual-layered metal-organic framework nanostructure UiO66-ZIF8 for enhanced cell imaging. UiO66-NH2 nanoparticles were synthesized as the template for MB loading, and the ZIF-8 shell was further coated on the surface of UiO66-MB to ensure its stability and lysosomal escape effect. Taking multidrug-resistant (MDR1) mRNA as a model target, MBs loaded within UiO66-ZIF8 showed an improved lysosomal escape effect compared with MB absorbed on UiO66-NH2. Therefore, efficient and accurate intracellular MDR1 mRNA imaging was realized with UiO66-MB-ZIF8. This work presented a new method for the rational regulation of the intracellular fate of MOF-based nanoprobes and will facilitate the further development of hierarchical MOF nanoprobes for analytical applications.

Inhibition of NLRP3 Protects Human Lens Epithelial Cells against Oxidative Stress-Induced Apoptosis by NF-κB Signaling.

BACKGROUNDS/AIMS: To explore whether NLRP3 is involved in the development of cataract and to study the effect of NLRP3 on hydrogen peroxide (H2O2)-induced injury in human lens epithelial cells. METHODS: Oxidative stress-induced apoptosis model was constructed by treating HLEB3 cells with 50 µM H2O2 at different times (6 h, 12 h) and was confirmed by flow cytometry and Western blot. HLEB3 were divided into NC, NC+H2O2, shNLRP3, and shNLRP3+H2O2 groups. Quantitative real-time polymerase chain reaction and Western blot were employed to detect mRNA and protein expressions, DCFH-DA to measure reactive oxygen species production, and Annexin V-FITC/PI staining to determine cell apoptosis. RESULTS: NLRP3 expression significantly increased in H2O2-induced HLEB3 cells. shRNA interference of NLRP3 inflammasome protects HLEB3 cells against oxidative stress-induced apoptosis by decreasing the expression levels of caspase-3 and Bax and increasing Bcl-2 expression. shNLRP3 was able to effectively suppress H2O2-induced apoptosis via inhibition of NF-κB signaling. CONCLUSION: NLRP3 might be involved in the apoptosis of lens epithelial cells. The inhibition of NLRP3 obviously attenuated H2O2-induced oxidative stress injury of human lens epithelial cells via NF-κB signaling.

A cancer cell membrane-camouflaged nanoreactor for enhanced radiotherapy against cancer metastasis.

We report a cancer cell membrane-camouflaged nanoreactor based on a GOx decorated TiO2@MnO2 core-shell structure for enhanced radiotherapy against cancer metastasis. The nanoreactor could specifically target tumor tissues, catalytically oxidize glucose to generate H2O2, and generate abundant ROS under X-ray irradiation.

A cancer cell membrane-encapsulated MnO2 nanoreactor for combined photodynamic-starvation therapy.

We demonstrate a MnO2-based nanoreactor to achieve continuous oxygen generation and efficient conversion from glucose to singlet oxygen for combined photodynamic-starvation therapy.

Parameters of ocular fundus on spectral-domain optical coherence tomography for glaucoma diagnosis.

In this review, we summarize the progression of several parameters assessed by spectral-domain optical coherence tomography (SD-OCT) in recent years for the detection of glaucoma. Monitoring the progression of defects in the retinal nerve fiber layer (RNFL) thickness is essential. Imaging and analysis of retinal ganglion cells (RGCs) and inner plexiform layer (IPL), respectively, have been of great importance. Optic nerve head (ONH) topography obtained from 3D SD-OCT images is another crucial step. Other important assessments involve locating the Bruch's membrane opening (BMO), estimating the optic disc size and rim area, and measuring the lamina cribrosa displacement. Still other parameters found in the past three years for glaucoma diagnosis comprise central retinal artery resistive index, optic disc perfusion in optical coherence tomography angiography (OCTA) study, peripapillary choroidal thickness, and choroidal area in SD-OCT. Recently, several more ocular fundus parameters have been found, and compared with the earlier parameters to judge the accuracy of diagnosis. While a few of these parameters have been widely used in clinical practice, a fair number are still in the experimental stage.