Guangjian Huang

Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function

Abstract Objective. Defective immune function is an important cause of tumor development. Accumulation of myeloid-derived suppressor cell (MDSC) associated with inhibition of dendritic cell (DC) function is one of the major immunological abnormalities in cancer. However, the molecular mechanism of the phenomenon remains unclear. Material and methods. We evaluated T cell stimulatory activity and interleukin (IL)-12 production of DC in a mouse model of liver cancer (hepatocellular carcinoma [HCC] mice). Then we detected the frequency of MDSC in spleen, peripheral blood (PB), lymph node (LN) and tumor tissue of HCC mice and its potential mechanisms. We also evaluated IL-10 production of MDSC and mechanism by which MDSC inhibit DC function. Results. Toll-like receptor (TLR)-ligand (LPS, CpG, poly(I:C))-induced IL-12 production of DC was decreased in HCC mice compared with control. The T cell stimulatory activity of DC was lower in HCC mice than in controls. Meanwhile, an increase in the frequency of MDSC in tumor development was detected in spleen, PB, LN and tumor, and the IL-10 levels were higher in HCC mice derived MDSC than in control. Furthermore, the MDSC inhibited TLR-ligand-induced IL-12 production of DC by IL-10 production and suppressed T cell stimulatory activity of DC. Finally, we demonstrated that the increase in the frequency of MDSC was mediated by MyD88–NF-kB pathway. Conclusions. Our study suggests a new role for MDSCs in HCC development by suppressing host immune responses, and these findings have important implications when designing immunotherapy protocols.

lncRNA GAS5 enhances G1 cell cycle arrest via binding to YBX1 to regulate p21 expression in stomach cancer

Long non-coding RNAs (lncRNAs), which have evolved as important gene expression modulators, are involved in human malignancies. The down-regulation of lncRNA growth arrest specific transcript 5 (GAS5) has been reported in several cancers, however, the underlying mechanism of lncRNA GAS5 in stomach cancer is poorly understood. In this study, we found that lncRNA GAS5 had lower expression in stomach cancer tissues than the normal counterparts. lncRNA GAS5 was shown to interact with Y-box binding protein 1 (YBX1), and lncRNA GAS5 knockdown was shown to accelerate YBX1 protein turnover without affecting YBX1 transcription. lncRNA GAS5 down-regulation reduced the YBX1 protein level, which decreased YBX1-transactivated p21 expression and abolished G1 phase cell cycle arrest in stomach cancer. These results delineate a novel mechanism of lncRNA GAS5 in suppressing stomach carcinogenesis, and the lncRNA GAS5/YBX1/p21 pathway we discovered may provide useful targets for developing lncRNA-based therapies for stomach cancer.

Scalable preparation of ultrathin silica-coated Ag nanoparticles for SERS application.

Silica-coated Ag nanoparticles (Ag@SiO2 NPs) have been successfully prepared by a scalable flame spray pyrolysis (FSP) technique with production rate up to 4 g/h in laboratory-scale. The ultrathin SiO2 shell, with a thickness 1 nm, not only effectively avoids the intersintering of Ag nanoparticles core at the high temperature, but also serves as a protective layer of the SERS-active nanostructure. The silica-coated Ag nanoparticles form agglomerates in the large temperature gradient zone, which with several nanometers gaps from each other but not contact. Such an intriguing feature can result in more Raman hot-spots generated at the gaps among Ag core active sites, which will beneficial for the whole SERS substrate enhancement. The results demonstrate that a maximum enhancement factor can reach ~10(5) with a detectable concentration as low as 10(-10) M for rhodamine 6G (R6G) molecules, indicating that the as-obtained unique nanostructure will be a promising candidate for SERS applications.

Multifunctional gadolinium-labeled silica-coated Fe3O4 and CuInS2 nanoparticles as a platform for in vivo tri-modality magnetic resonance and fluorescence imaging

The facile fabrication of Gd-labeled superparamagnetic Fe3O4 nanoparticles (NPs) and fluorescent CuInS2 (CIS) quantum dots conjugated with arginine-glycine-aspartic acid (RGD) peptides has been demonstrated, for tri-mode targeted T1-, T2-weighted magnetic resonance (MR) and fluorescence imaging of pancreatic cancer. The core-shell nanocomposites formed are water-dispersible, stable and biocompatible, as confirmed by MTT assay on BXPC-3 cells. Relaxivity measurements show a T1 relaxivity (r1) of 1.56 mM-1 s-1 and a T2 relaxivity (r2) of 23.22 mM-1 s-1, which enable T1- and T2-weighted MR imaging of cancer cells in vitro and in vivo. The MR imaging data clearly indicate that the multifunctional NPs can specifically target cancer cells with αvβ3 integrin over-expression on the cell surface, through a receptor-mediated delivery pathway. The T1-weighted positive and T2-weighted negative enhancement in the MR imaging significantly improves the diagnosis accuracy, and fluorescence imaging of tumor tissue can assist in clinical surgery. These findings suggest that these multifunctional NPs could be used as a platform for bimodal imaging (both MR and fluorescence) in various biological systems.

LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer

Angiogenesis can aggravate gastric cancer progression. LncRNAs exert important roles in regulating various cancer behaviors. However, the functions and mechanisms of lncRNAs in angiogenesis remain largely unknown. Here we demonstrated that lncRNA PVT1 was upregulated and significantly associated with high-microvessel density and poor prognosis in gastric cancer. Through gain- and loss-of PVT1 expression, we found PVT1 could obviously induce angiogenesis within tumors, in addition to promoting tumor growth in vitro and in vivo. Mechanistically, PVT1 directly interacted with the signal transducer activator phospho-STAT3 in the nucleus, and increased its protein stability by protecting it from poly-ubiquitination and proteasome-dependent degradation. The binding of PVT1 activated the STAT3 signalling pathway, and successively elevated VEGFA expression to stimulate angiogenesis. The positive correlation of PVT1 and VEGFA expression was also verified in gastric cancer specimens, and high levels of PVT1 and VEGFA in combination frequently predicted shorter survival time. Moreover, we revealed that PVT1 was a STAT3-responsive lncRNA, as STAT3 could occupy the PVT1 promoter to facilitate its transcription. The positive feed-back loop of PVT1 and STAT3 continuously enhanced the oncogenic effects. Collectively, our study first elucidates the mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis, which provides promising target for developing new therapeutic strategy in gastric cancer.

Comprehensive Analysis of Vascular Endothelial Growth Factor-C Related Factors in Stomach Cancer

BACKGROUND Vascular endothelial growth factor-C (VEGF-C), which contributes to lymphatic metastasis (LM) in malignant disease, is one of the most important factors involved in physical and pathological lymphangiogenesis. Some VEGF-C related factors such as sine oculis homeobox homolog (SIX) 1, contactin (CNTN) 1 and dual specificity phosphatase (DUSP) 6 have been extensively studied in malignancies, but their expression levels and associations have still to be elucidated in stomach cancer. METHODS We detected their expression levels in 30 paired stomach cancer tissues using quantitative real-time reverse transcription-PCR (qRT-PCR). The expression and clinical significance of each factor was analyzed using Wilcoxon signed rank sum test. The correlation among all the factors was performed by Spearman rank correlation analysis. RESULTS The results suggest that VEGF-C and CNTN1 are significantly correlated with tumor size, SIX1 with the age and CNTN1 also with the cTNM stage. There are significant correlations of expression levels among VEGF-C, SIX1, CNTN1 and DUSP6. CONCLUSIONS There exists an important regulatory crosstalk involving SIX1, VEGF-C, CNTN1 and DUSP6 in stomach cancer.

Help nanorods “stand” on microsubstrate to form hierarchical ZnO nanorod-nanosheet architectures

ZnO nanorods were helped to “stand” vertically on microsubstrates by an interesting seed-mediated approach. Taking ZnO nanosheets as the microsubstrates, ZnO nanorods can grow vertically, not lying horizontally, on the facets with the aid of a seed layer precoating to form hierarchical ZnO nanorod-nanosheet architectures. The diameter as well as the length of the standing nanorods can be controlled effectively by adjusting the growth time and ammonia amount in the growth solution. The precoated seed layer has been found to be the key factor in determining the resultant morphology. Room-temperature photoluminescence studies revealed that the near band-edge (NBE) emission intensity of the hierarchical architectures was increased greatly compared with that of bare ZnO nanosheets. These special hierarchical architectures make them appealing for future microdevice applications.

Sine Oculis Homeobox Homolog 1 Regulates Mitochondrial Apoptosis Pathway Via Caspase-7 In Gastric Cancer Cells

Sine oculis homeobox homolog 1 (Six1) is crucial in normal organ development. Recently, Six1 is reported to display aberrant expression in various cancers and plays important roles in cancer development. However, the regulatory mechanism of Six1 in gastric cancer is largely unknown. In the current study, we found that Six1 was increased in gastric cancer tissues, and its upregulation significantly associated with lymph node metastasis (p=0.042) and poor differentiation (p=0.039). Next, we took advantage of public available microarray data to assess Six1 prognostic value with online K-M Plotter software in gastric cancer, which demonstrated that patients with higher Six1 expression had shorter survival time (p=0.02). To explore the underlying mechanism of Six1, we silenced its upregulation in gastric cells to detect cellular functions. Our results indicated that knock-down Six1 could decrease colony formation number and rendered cells sensitive to 5- Fluorouracil drug treatment. The flow cytometry analyses showed that Six1 silence could promote apoptosis but had little effect on cell cycle transition. Along this clue, we tested mitochondrial membrane potential with JC-1 assay, which suggested that Six1 inhibition could trigger mitochondrial apoptosis. Our subsequent results revealed that Six1 knock-down could reduce the level of anti-apoptotic protein Bcl-2, and caspase-7 but not caspase-3 was involved to execute the mitochondrial apoptosis pathway. Taken together, we find Six1 has oncogenic role in gastric cancer development, and silenced Six1 expression can promote mitochondrial apoptosis by repressing Bcl-2 and activating executor caspase-7. These findings suggest that Six1 may become a valuable prognostic and therapeutic target in gastric cancer.

The Diverse Mechanisms of miRNAs and lncRNAs in the Maintenance of Liver Cancer Stem Cells

Liver cancer is the second leading cause of cancer-related death worldwide. The high frequency of recurrence and metastasis is the main reason for poor prognosis. Liver cancer stem cells (CSCs) have unlimited self-renewal, differentiation, and tumor-regenerating capacities. The maintenance of CSCs may account for the refractory features of liver cancer. Despite extensive investigations, the underlying regulatory mechanisms of liver CSCs remain elusive. miRNA and lncRNA, two major classes of the ncRNA family, can exert important roles in various biological processes, and their diverse regulatory mechanisms in CSC maintenance have acquired increasing attention. However, to the best of our knowledge, there is a lack of reviews summarizing these findings. Therefore, we systematically recapitulated the latest studies on miRNAs and lncRNAs in sustaining liver CSCs. Moreover, we highlighted the potential clinical application of these dysregulated ncRNAs as novel diagnostic and prognostic biomarkers and therapeutic targets. This review not only sheds new light to fully understand liver CSCs but also provides valuable clues on targeting ncRNAs to block or eradicate CSCs in cancer treatment.