Transcription factor c-Jun modulates GLUT1 in glycolysis and breast cancer metastasis.

As the main isoforms of membranous glucose transporters (GLUT), GLUT1 involves tumorigenesis, metastasis and prognosis in a variety of cancers. However, its role in breast cancer metastasis remains to be elucidated. Here we examined its transcriptional and survival data in patients with breast cancer from several independent databases including the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression across Normal and Tumor tissue, UALCAN, cBioPortal, Kaplan-Meier Plotter and PROGgeneV2. We found that its mRNA expression was significantly high in cancer tissues, which was associated with metastasis and poor survival. Transcription factor c-Jun might bind to GLUT1 promoter to downregulate its gene expression or mRNA stability, therefore to suppress glycolysis and metastasis. By qRT-PCR, we verified that GLUT1 was significantly increased in 38 paired human breast cancer samples while JUN was decreased. Furthermore, the protein level of GLUT1 was higher in tumor than in normal tissues by IHC assay. To explore underlying pathways, we further performed GO and KEGG analysis of genes related to GLUT1 and JUN and found that GLUT1 was increased by transcription factor c-Jun in breast cancer tissues to influence glycolysis and breast cancer metastasis.

tRNA-derived fragment tRFLys-CTT-010 promotes triple-negative breast cancer progression by regulating glucose metabolism via G6PC.

tRNA-derived fragments (tRFs) are a novel class of small non-coding RNAs whose biological roles are not well defined. Here, using multiple approaches, we investigated its role in human triple-negative breast cancer (TNBC). Our genome-wide transcriptome analysis of small non-coding RNAs revealed that tRFLys-CTT-010 was significantly increased in human TNBC. It promoted TNBC proliferation and migration. It also closely associated with starch and sucrose metabolism pathways (Kyoto Encyclopedia of Genes and Genomes analysis) and positively regulated the expression of glucose-6-phosphatase catalytic subunit (G6PC), one of the related genes in the pathway. G6PC, a complex of glucose-6-phosphatase in gluconeogenesis and glycogenolysis, is upregulated in human TNBC samples. Further studies demonstrated that overexpression of G6PC in tRFLys-CTT-010 inhibitor-transfected TNBC cell lines can reverse malignant biological behavior and knockdown of G6PC in TNBC cell lines inhibited tumor progression and reversed the oncogenic function of tRFLys-CTT-010. In addition, tRFLys-CTT-010 interacted with G6PC to regulate cellular lactate production and glycogen consumption, resulting in cell survival and proliferation. Thus, fine-tuning glucose metabolism and the tRFLys-CTT-010/G6PC axis may provide a therapeutic target for TNBC treatment.

lncRNA APOC1P1-3 promoting anoikis-resistance of breast cancer cells.

BACKGROUND: Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibit apoptosis of breast cancer cells. In this study, we explored its role in anoikis resistance. METHODS: We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture conditions and studied lncRNA APOC1P1-3 effects on apoptosis. Using Dual-Luciferase activity assay, we determined whether it specifically binds to miRNA-188-3P. We further explored its role in lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in female BALB/c nude mice. RESULTS: We found that lncRNA APOC1P1-3 suppressed early apoptosis of these cells (demonstrated by gain or loss of their function, respectively) and promoted anoikis resistance via reducing activated- Caspase 3, 8, 9 and PARP. Moreover, it specifically binds to the target miRNA-188-3p acting as a "sponge" to block the inhibition of Bcl-2 (an anti-apoptosis protein). CONCLUSIONS: Our study supports a theory that lncRNA APOC1P1-3 can promote development of breast cancer metastasis via anoikis resistance by specifically binding to miRNA-188-3p to block the inhibition of Bcl-2.

A universal growth strategy for DNA-programmed quantum dots on graphene oxide surfaces.

The emerging materials of semiconductor quantum dots/graphene oxide (QDs/GO) hybrid composites have recently attracted intensive attention in materials science and technology due to their potential applications in electronic and photonic devices. Here, a simple and universal strategy to produce DNA-programmed semiconductor quantum dots/graphene oxide (QDs/GO) hybrid composites with controllable sizes, shapes, compositions, and surface properties is reported. This proof-of-concept work successfully demonstrates the use of sulfhydryl modified single-stranded DNA (S-ssDNA) as a 'universal glue' which can adsorb onto GO easily and provide the growth sites to synthesize CdS QDs, CdSe QDs, CdTe QDs and CdTeSe QDs with distinctive sizes, shapes and properties. Also, adapting this method, other graphene oxide-based hybrid materials which are easily synthesized in aqueous solution, including oxides, core-shell structure QDs and metal nanocrystals, would be possible. This method provided a universal strategy for the synthesis and functional realization of graphene -based nanomaterials.

CRISPR/Cas9 Mediated Deletion of the Uox Gene Generates a Mouse Model of Hyperuricemia with Multiple Complications.

Hyperuricemia is a common metabolic disorder with severe complications. We aimed to develop a mouse model for spontaneous hyperuricemia. Uox-/- mouse model was generated on C57BL/6J background by deleting exon 2-4 of Uox using the CRISPR/Cas9 system. The prototypic Uox -/-mice had 5.5-fold increased serum uric acid (1351.04±276.58µmol/L) as compared to the wild type mice (P<0.0001), but died by 4 weeks. After allopurinol (3ug/g) intervention, they all survived > 8 weeks. The serum uric acid was 612.55±146.98µmol/L in the 8-week-old allopurinol-rescued Uox -/-mice, which manifested multiple complications including severe renal insufficiency, hypertension, left ventricular remodeling and systolic dysfunction, aortic endothelial dysfunction, hepatic steatosis and elevated liver enzymes, as well as hyperglycemia and hypercholesteremia. The present Uox-/- mice developed spontaneous hyperuricemia complicated with urate nephropathy, cardiovascular disease and cardiometabolic disorders, and may provide a novel tool to study hyperuricemia associated early-onset cardiovascular disorders in human.

Construction of multifunctional carboxymethyl cellulose nanohydrogel carriers based on near-infrared DNA-templated quantum dots for tumor theranostics.

Multifunctional therapeutic platforms with targeted delivery, fast diagnosis, and efficient therapy could effectively reduce side effects and improve treatment in the clinical therapy of tumors. Near-infrared DNA-templated CdTeSe quantum dots (DNA-CdTeSe QDs) were developed as building blocks to construct a multifunctional carboxymethyl cellulose (CMC)-based nanohydrogel as a nanocarrier to address the challenges of serious side effects and precise treatment in cancer theranostics, including active tumor targeting, fluorescence tracking, controlled drug release, chemotherapy and gene regulation. Single-stranded DNA containing the complementarity sequence of miRNA and cystine, as co-crosslinkers, initiated hybridization between the DNA-CdTeSe QD-modified CMC chain with the anti-nucleolin aptamer DNA (AS1411)-modified CMC chain to form the hydrogels. DOX, as a model drug, was successfully incorporated into the hydrogels. The synthesized multifunctional hydrogel nanocarriers with an average diameter of 150 nm could be taken up through targeting and achieved the controlled release of DOX by triggering both glutathione (GSH) and miRNA in the tumor microenvironment. The CdTeSe QDs trapped in nanohydrogels acted as fluorophores for bioimaging in the diagnosis and treatment process. The proposed multifunctional delivery system provided a potential platform for tumor imaging and precise therapy.

Anti-cancer Drug Anlotinib Promotes Autophagy and Apoptosis in Breast Cancer.

BACKGROUND: Anlotinib, a multi-target tyrosine kinase inhibitor, has significant anti-cancer effects on breast cancer (BC), lung cancer, colon cancer and ovarian cancer, but its mechanism has not been investigated in BC. METHODS: The cell viability and growth of human non-triple negative BC cell line MCF-7 and triple negative BC cell line MDA-MB-231 with the treatment of anlotinib were tested by Cell Counting Kit-8 (CCK-8) assay and Ki67 staining. The alteration of genes related to apoptosis and autophagy were investigated by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), western blots and immunocytochemistry (ICC). Cell apoptosis was valued by TUNEL staining and flow cytometry. Further, mouse breast tumour cell lines AT-3 cells were subcutaneously injected into C57BL/6 mice, and the effect of anlotinib intragastrically on tumour growth in vivo was examined. RESULTS: We found that anlotinib suppressed the cell viability and depressed Ki67 staining in MCF-7 and MDA-MB-231 cell lines. Besides, the drug also enhanced cell autophagy and apoptosis of MCF-7 and MDA-MB-231 cell lines, which could be rescued by autophagy inhibitors wortmannin (wort) and 3-methyladenine (3-MA), and BECN1 knockdown. Furthermore, Akt/GSK-3α pathway was inactivated by anlotinib treatment, while rescued by wort, 3-MA and silencing of BECN1 in the MCF-7 or MDA-MB-231 cells. We also found that anlotinib inhibited implanted tumour growth of BC in syngeneic mice. CONCLUSIONS: Our study demonstrated that anlotinib inhibited breast cancer cell growth in vitro and in vivo. Anlotinib promoted cell apoptosis and inactivated Akt/GSK-3α pathway of BC cells by inducing cell autophagy. It indicated that anlotinib may be an effective new drug for BC treatment.

Aptamer-mediated DNA concatemer functionalized magnetic nanoparticles for reversible capture and release of circulating tumor cells.

Effectively capturing, releasing, and reanalyzing circulating tumor cells (CTCs) are critical in cancer diagnosis and individualized treatment. Traditional immunomagnetic separation has disadvantages of low sensitivity and specificity, and is time-consuming and costly in CTCs capture. It is also easily disturbed by the microenvironment in releasing and analyzing CTCs. Here, we proposed an aptamer-mediated DNA concatemer functionalized magnetic nanoparticles (MNPs-AMDC) for the reversible capture and release of CTCs. In this study, aptamers were used both for efficiently capturing CTCs without complicated assembly steps and stimulus-response switch for releasing CTCs with little influence on cellular activity. The MNPs-AMDC was demonstrated to effectively capture (83%) and release CTCs with a good viability rate (92%). Moreover, this device was also tested in clinical blood samples, which would provide a universal tool for diagnosing cancer and treating individuals.

Wearable Virtual White Cane Network for navigating people with visual impairment.

Navigating the world with visual impairments presents inconveniences and safety concerns. Although a traditional white cane is the most commonly used mobility aid due to its low cost and acceptable functionality, electronic traveling aids can provide more functionality as well as additional benefits. The Wearable Virtual Cane Network is an electronic traveling aid that utilizes ultrasound sonar technology to scan the surrounding environment for spatial information. The Wearable Virtual Cane Network is composed of four sensing nodes: one on each of the user's wrists, one on the waist, and one on the ankle. The Wearable Virtual Cane Network employs vibration and sound to communicate object proximity to the user. While conventional navigation devices are typically hand-held and bulky, the hands-free design of our prototype allows the user to perform other tasks while using the Wearable Virtual Cane Network. When the Wearable Virtual Cane Network prototype was tested for distance resolution and range detection limits at various displacements and compared with a traditional white cane, all participants performed significantly above the control bar (p < 4.3 × 10(-5), standard t-test) in distance estimation. Each sensor unit can detect an object with a surface area as small as 1 cm(2) (1 cm × 1 cm) located 70 cm away. Our results showed that the walking speed for an obstacle course was increased by 23% on average when subjects used the Wearable Virtual Cane Network rather than the white cane. The obstacle course experiment also shows that the use of the white cane in combination with the Wearable Virtual Cane Network can significantly improve navigation over using either the white cane or the Wearable Virtual Cane Network alone (p < 0.05, paired t-test).

A Simple and Inexpensive Stereotactic Guidance Frame for MRI-Guided Brain Biopsy in Canines.

A magnetic resonance imaging (MRI) guided stereotactic system was developed to provide veterinarians a method to accomplish minimally invasive stereotactic brain biopsies and procedures involving the cerebrum in canines. While MR-guided procedures are prevalent for humans, they are less common in animal practices. The system was designed to minimize fabrication costs in an effort to make such procedures more accessible in the veterinary field. A frame constrained the head without the need for punctures and supported registration and guidance attachments. Location data for registration and relevant structures were selected by the clinician, and a reverse kinematic analysis program generated the settings of the stereotactic arch to guide a needle to the desired location. Phantom experiments and three cadaver trials showed an average targeting error of <3 mm using the system.