Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability.

PURPOSE: Sialic acid-bound immunoglobulin-like lectin 15 (Siglec15) has emerged as a novel therapeutic target in tumor immunotherapy. This study is designed to investigate the function and mechanism of Siglec15 in thyroid carcinoma (THCA). MATERIALS AND METHODS: The information on patients with THCA from TGCA and GEO database were used to analyze the expression of Siglec15 in THCA. THCA cells were treated with Siglec15-mFc, a recombinant fusion protein consisting of the extracellular domain of human Siglec15 and murine IgG Fc. THP-1 cells expressing human Siglec15 and its mutant were co-cultured with THCA cells to mimic the contact between Siglec15-expressing tumor-associated macrophages and THCA cells. Wound-healing assay and transwell migration assay were used to examine the migration abilities of BCPAP and C643 cells. Pull-down assay was performed to examine the interaction between Siglec15 and epidermal growth factor receptor (EGFR) on the cancer cells. Cycloheximide (CHX) assay was used to evaluate the stability of the protein. RESULTS: The expression of Siglec15 in thyroid carcinoma tissues is higher than in normal tissues. Siglec15 promotes the migration of THCA cells by binding to EGFR in a sialic acid-dependent manner and increases EGFR protein expression. Inhibition of the EGFR pathway blocks the effect of Siglec15 on the migration of THCA cells. CONCLUSIONS: Our findings reveals that Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability.

The Interaction between DNMT1 and High-Mannose CD133 Maintains the Slow-Cycling State and Tumorigenic Potential of Glioma Stem Cell.

The quiescent/slow-cycling state preserves the self-renewal capacity of cancer stem cells (CSCs) and leads to the therapy resistance of CSCs. The mechanisms maintaining CSCs quiescence remain largely unknown. Here, it is demonstrated that lower expression of MAN1A1 in glioma stem cell (GSC) resulted in the formation of high-mannose type N-glycan on CD133. Furthermore, the high-mannose type N-glycan of CD133 is necessary for its interaction with DNMT1. Activation of p21 and p27 by the CD133-DNMT1 interaction maintains the slow-cycling state of GSC, and promotes chemotherapy resistance and tumorigenesis of GSCs. Elimination of the CD133-DNMT1 interaction by a cell-penetrating peptide or MAN1A1 overexpression inhibits the tumorigenesis of GSCs and increases the sensitivity of GSCs to temozolomide. Analysis of glioma samples reveals that the levels of high-mannose type N-glycan are correlated with glioma recurrence. Collectively, the high mannose CD133-DNMT1 interaction maintains the slow-cycling state and tumorigenic potential of GSC, providing a potential strategy to eliminate quiescent GSCs.

Siglec-15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44.

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has been identified as a novel potential target for cancer immunotherapy. Here, we explored the role of Siglec-15 in human hepatoma cells. In this study, we found that the expression of Siglec-15 is substantially upregulated in liver cancer tissues in comparison with the nontumor tissues. Functionally, in vitro experiments show that Siglec-15 promotes the migration of hepatoma cells. Furthermore, the data demonstrated an interaction between Siglec-15 and CD44, a transmembrane glycoprotein that mediates tumor progression and metastasis. In addition, we show that CD44 is modified by α2,6-linked sialic acids on N-glycans in hepatoma cells and that CD44 sialylation affects its interaction with Siglec-15. Removal of the sialic acid residues from CD44 resulted in suppressed interaction between Siglec-15 and CD44. We further demonstrate that Siglec-15 interacts and promotes the stability of CD44 by preventing its lysosomal-mediated degradation. Taken together, our findings demonstrate that Siglec-15 promotes the migration of hepatoma cells by regulating the CD44 protein stability.

The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells.

The tumor-initiating cell (TIC) marker CD133 promotes TIC self-renewal and tumorigenesis through the tyrosine phosphorylation of its c-terminal domain. Therefore, finding compounds that target the phosphorylation of CD133 will provide an effective method for inhibiting TICs characteristics. Here, through small molecule microarray screening, compound LDN193189 was found to bind to the c-terminus of CD133 and influenced its tyrosine phosphorylation. LDN193189 inhibited the interaction between CD133 and p85, accompanied by a reduction in the self-renewal and tumorigenicity of liver TIC. In addition, LDN193189 inhibited the expression and transcription of Galectin-3 by reducing the tyrosine phosphorylation of CD133. Galectin-3 secreted by liver TICs inhibited the proliferation of activated CD8+ T cells by binding to PD-1. LDN193189 suppressed the immune escape ability of liver TICs by downregulating Galectin-3. Taken together, LDN193189 suppressed the tumorigenesis and immune escape of liver CSCs by targeting the CD133-Galectin-3 axis.

Field Screening of Rice Germplasm (Oryza sativa L. ssp. japonica) Based on Days to Flowering for Drought Escape.

Terminal drought stress is one of the restrictive factors in rice production and is expected to upsurge under the current situation of climate change. The study evaluated the performance of 2030 rice genotypes under continuous drought stress conditions based on days to flowering (DF). The genotypes under augmented randomized complete block design were sown in May/June of 2017 and 2018 in the field with movable rainout that resulted in huge genetic diversity among the accessions. Descriptive statistics confirmed clear variation among accessions on growth duration, plant height to leaf, plant height to panicle, and germination percentage. Correlation, chemometric, and agglomerative hierarchical cluster analyses were performed that categorized the germplasm into 10 groups. Genotypes in clusters VIII and IX (drought-resistant) revealed better agronomic performance in terms of reduced days to flowering, but conversely taller plant height and higher maturity (%) under severe stress. Genotypes in clusters IV, V, and X were discovered to be drought-susceptible. The screened genotypes like Longjing 12, Longdun 102, Yanjing 22, Liaojing 27, Xiaohongbandao, Songjing 17, and Zaoshuqingsen can be utilized in rice breeding improvement programs for drought tolerance in terms of severe continuous drought, as well as terminal drought stress.

Exosomes isolated from CAPS1­overexpressing colorectal cancer cells promote cell migration.

Calcium­dependent activator protein for secretion 1 (CAPS1) has been reported to promote metastasis in colorectal cancer (CRC), however, the underlying mechanisms have not yet been elucidated. The present study revealed that exosomes derived from CAPS1­overexpressing CRC cells could enhance the migration of normal colonic epithelial FHC cells. GW4869, an inhibitor of exosomes, could attenuate the migration of FHC cells. Furthermore, liquid chromatography­mass spectrometry (LC­MS) and bioinformatics analysis demonstrated that overexpression of CAPS1 could alter the expression pattern of exosomal proteins involved in cell migration. Bone morphogenetic protein 4, which may serve vital roles in the process of CAPS1­induced cell migration, was downregulated in the exosomes. In summary, the present results demonstrated that CAPS1 promotes cell migration by regulating exosomes. Inhibiting the secretion of exosomes may be helpful for the treatment of patients with metastatic CRC.

Prognostic Value of Tumor Heterogeneity on 18F-FDG PET/CT in HR+HER2- Metastatic Breast Cancer Patients receiving 500 mg Fulvestrant: a retrospective study.

Heterogeneity has been demonstrated to be a predictor of treatment failure and drug resistance. Our study aimed to investigate imaging parameters, including tumor heterogeneity, as prognostic factors of response to 500 mg fulvestrant using 18F-FDG PET/CT. Twenty-seven estrogen receptor (HR)-positive/HER2-negative metastatic breast cancer patients who received 500 mg fulvestrant and underwent 18F-FDG PET/CT before treatment were retrospectively included. In PET/CT scans, conventional parameters (maximum and mean standardized uptake value, metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and heterogeneity parameters (intra-tumor heterogeneity index [HI] and inter-tumor heterogeneity coefficient of variation [COV]) were analyzed. Progression-free survival (PFS) was mainly assessed for efficacy. The survival analyses were performed using the Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazard model. Univariate analysis indicated that a high SUVmax and a high tumor HI at baseline were associated with longer PFS of fulvestrant (P = 0.036 and P = 0.033, respectively). Liver metastasis, SUVmax and HI were statistically significant in multivariate analysis (P values of 0.017, 0.025 and 0.043, respectively). 18F-FDG based intra-tumor heterogeneity appears to be a potential predicator of efficacy of fulvestrant among HR+HER2- metastatic breast cancer patients.

Establishment of a 12-gene expression signature to predict colon cancer prognosis.

A robust and accurate gene expression signature is essential to assist oncologists to determine which subset of patients at similar Tumor-Lymph Node-Metastasis (TNM) stage has high recurrence risk and could benefit from adjuvant therapies. Here we applied a two-step supervised machine-learning method and established a 12-gene expression signature to precisely predict colon adenocarcinoma (COAD) prognosis by using COAD RNA-seq transcriptome data from The Cancer Genome Atlas (TCGA). The predictive performance of the 12-gene signature was validated with two independent gene expression microarray datasets: GSE39582 includes 566 COAD cases for the development of six molecular subtypes with distinct clinical, molecular and survival characteristics; GSE17538 is a dataset containing 232 colon cancer patients for the generation of a metastasis gene expression profile to predict recurrence and death in COAD patients. The signature could effectively separate the poor prognosis patients from good prognosis group (disease specific survival (DSS): Kaplan Meier (KM) Log Rank p = 0.0034; overall survival (OS): KM Log Rank p = 0.0336) in GSE17538. For patients with proficient mismatch repair system (pMMR) in GSE39582, the signature could also effectively distinguish high risk group from low risk group (OS: KM Log Rank p = 0.005; Relapse free survival (RFS): KM Log Rank p = 0.022). Interestingly, advanced stage patients were significantly enriched in high 12-gene score group (Fisher's exact test p = 0.0003). After stage stratification, the signature could still distinguish poor prognosis patients in GSE17538 from good prognosis within stage II (Log Rank p = 0.01) and stage II & III (Log Rank p = 0.017) in the outcome of DFS. Within stage III or II/III pMMR patients treated with Adjuvant Chemotherapies (ACT) and patients with higher 12-gene score showed poorer prognosis (III, OS: KM Log Rank p = 0.046; III & II, OS: KM Log Rank p = 0.041). Among stage II/III pMMR patients with lower 12-gene scores in GSE39582, the subgroup receiving ACT showed significantly longer OS time compared with those who received no ACT (Log Rank p = 0.021), while there is no obvious difference between counterparts among patients with higher 12-gene scores (Log Rank p = 0.12). Besides COAD, our 12-gene signature is multifunctional in several other cancer types including kidney cancer, lung cancer, uveal and skin melanoma, brain cancer, and pancreatic cancer. Functional classification showed that seven of the twelve genes are involved in immune system function and regulation, so our 12-gene signature could potentially be used to guide decisions about adjuvant therapy for patients with stage II/III and pMMR COAD.

Performance of GaN-based light-emitting diodes fabricated using GaN epilayers grown on silicon substrates.

Light extraction of GaN-based light-emitting diodes grown on Si(111) substrate (GaN-on-Si based LEDs) is presented in this study. Three different designs of GaN-on-Si based LEDs with the lateral structure, lateral structure on mirror/Si(100) substrate, and vertical structure on mirror/Si(100) substrate were epitaxially grown by metalorganic chemical vapor deposition and fabricated using chemical lift-off and double-transfer techniques. Current-voltage, light output power, far-field radiation patterns, and electroluminescence characteristics of these three LEDs were discussed. At an injection current of 700 mA, the output powers of LEDs with the lateral structure on mirror/Si(100) substrate and vertical structure on mirror/Si(100) substrate were measured to be 155.07 and 261.07 mW, respectively. The output powers of these two LEDs had 70.63% and 187.26% enhancement compared to that of LED with the lateral structure, respectively. The result indicated this vertical structure LED was useful in improving the light extraction due to an enhancement in light scattering efficiency while the high-reflection mirror and diffuse surfaces were employed.

P-side up AlGaInP-based light emitting diodes with dot-patterned GaAs contact layers.

High-brightness p-side up AlGaInP-based red light emitting diodes (LEDs) with dot-patterned GaAs contact layer and surface rough structure are presented in this article. Initial LED structure of p-GaP/AlGaInP/GaAs is epitaxially grown using metal organic chemical vapor deposition technique. Using novel twice transferring process, the p-GaP layer is remained at the top side as both the current spreading and-window layer. Dot patterned GaAs contact dots are formed between main structure and rear mirror to improve light reflection and current spreading. Moreover, the surface of p-GaP window is further textured by nano-sphere lithography technique for improving the light extraction. Significant improvement in output power is found for AlGaInP LEDs with GaAs contact dots and roughened p-GaP window as compared with those of LEDs with traditional n-side up and p-side up structures without roughened surfaces.

Effects of crystallinity and point defects on optoelectronic applications of ß-Ga2O3 epilayers.

This study evaluates the effect of crystallinity and point defects on time-dependent photoresponsivity and the cathodoluminescence (CL) properties of ß-Ga2O3 epilayers. A synchrotron high-resolution X-ray technique was used to understand the crystalline structure of samples. Rutherford backscattering spectroscopy was used to determine the net chemical composition of the samples to examine the type and ratio of their possible point defects. The results show that in functional time-dependent photoresponsivity of photodetectors based on ß-Ga2O3 epilayers, point defects contribution overcomes the contribution of crystallinity. However, the crystalline structure affects the intensities and emission regions of CL spectra more than point defects.