Tumor-associated macrophages promote epithelial-mesenchymal transition and the cancer stem cell properties in triple-negative breast cancer through CCL2/AKT/ß-catenin signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. METHODS: Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. RESULTS: Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C-C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of ß-catenin. Furthermore, ß-catenin knockdown reversed TAM-induced EMT and CSC properties. CONCLUSIONS: This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/ß-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract.

Detection of the Deep-Sea Plankton Community in Marine Ecosystem with Underwater Robotic Platform.

Variations in the quantity of plankton impact the entire marine ecosystem. It is of great significance to accurately assess the dynamic evolution of the plankton for monitoring the marine environment and global climate change. In this paper, a novel method is introduced for deep-sea plankton community detection in marine ecosystem using an underwater robotic platform. The videos were sampled at a distance of 1.5 m from the ocean floor, with a focal length of 1.5-2.5 m. The optical flow field is used to detect plankton community. We showed that for each of the moving plankton that do not overlap in space in two consecutive video frames, the time gradient of the spatial position of the plankton are opposite to each other in two consecutive optical flow fields. Further, the lateral and vertical gradients have the same value and orientation in two consecutive optical flow fields. Accordingly, moving plankton can be accurately detected under the complex dynamic background in the deep-sea environment. Experimental comparison with manual ground-truth fully validated the efficacy of the proposed methodology, which outperforms six state-of-the-art approaches.

Circ-FOXO3 inhibits triple-negative breast cancer growth and metastasis via regulating WHSC1-H3K36me2-Zeb2 axis.

Circular RNAs (circRNAs), a subclass of non-coding RNAs characterized by covalently closed continuous loops, play a key role in tumorigenesis and aggressiveness. However, the potential molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remains largely unknown. Exploring their roles and mechanisms in TNBC progression may help identify new diagnostic markers and therapeutic targets. In this study, we found that circ-FOXO3 was dramatically downregulated in TNBC tissues and blood samples from patients with TNBC. Notably, low circ-FOXO3 expression in TNBC tissues and bloods was associated with lymph node metastasis and unfavorable outcomes in patients with TNBC. Overexpression of circ-FOXO3 significantly inhibited the growth, invasion, and metastasis of TNBC cells both in vitro and in vivo. Moreover, we demonstrated that circ-FOXO3 was predominantly expressed in the cytoplasm and directly interacted with Wolf-Hirschhorn syndrome candidate 1 (WHSC1), thereby inhibiting WHSC1 nuclear localization and activity, resulting in the inhibition of H3K36me2 modifications at the Zeb2 promoter, ultimately inhibiting Zeb2 expression and halting TNBC growth and metastasis. Taken together, these results reveal the tumor-suppressive functions of circ-FOXO3 in inhibiting WHSC1-mediated H3K36me2 modification of Zeb2, suggesting that circ-FOXO3 could serve as a potential novel predictive prognostic biomarker and therapeutic target for TNBC.

[FOXC1 Knockdown Reverses Gefitinib Resistance in Non-small Cell Lung Cancer].

BACKGROUND: Lung cancer is the malignant tumor with the highest incidence and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for about 80%. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapy has been playing an important role in treatment of NSCLC. However, unavoidable therapeutic resistance significantly limits the clinical efficacy of EGFR-TKI. As a key member of the forkhead box protein family, FOXC1 is aberrantly expressed in NSCLC and involved in NSCLC progression. The aim of this work is to investigate the effect and potential mechanism of FOXC1 on gefitinib resistance in NSCLC. METHODS: Western blot was performed to assess the expression of FOXC1 protein in HCC827/GR cells. Immunohistochemistry (IHC) assays were performed in human NSCLC tissues with gefitinib resistance. HCC827/GR cells were transfected with shRNA specifically targeting FOXC1 mRNA and stable cell lines were established. The effects of FOXC1 on cell viability and apoptosis were analyzed using a new methyl thiazolyl tetrazolium assay (MTS assay) and flow cytometry. Self-renewal ability was determined by mammosphere-formation analysis. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to detect the expression of SOX2, Nanog, OCT4 and CD133. Flow cytometry analysis were further used to detect the level of CD133. IHC assays were used to detect the levels of SOX2 and CD133 in NSCLC tissues with genfitiinb resistance. Correlations of the expressions of FOXC1, CD133 and SOX2 with each other in lung adenocarcinoma samples were analyzed based on The Cancer Genome Atlas (TCGA) database. RESULTS: The expression of FOXC1 is significantly increased in HCC827/GR cells compared with HCC827 cells (P<0.05). IHC results showed FOXC1 was highly expressed in NSCLC tissues with gefitinib resisitance. Knockdown of FOXC1 significantly increased the sensitivity of HCC827/GR cells to gefitinib. The cell viability was decreased and the apoptosis was promoted (P<0.05). Moreover, FOXC1 knockdown apparently inhibited the expression of SOX2 and CD133, and decreased the mammosphere-formation capacity in HCC827/GR cells. In NSCLC tissues with gefitinib resistance, the expressions of SOX2 and CD133 were significantly higher compared with gefitinib-sensitive tissues (P<0.01). Meanwhile, the expressions of FOXC1, CD133 and SOX2 with each other were positively correlated (P<0.05). CONCLUSIONS: FOXC1 could increase gefitinib resitance in NSCLC, by which mechanism is related to the regulation of cancer stem cell properties.

ß-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Though advances in diagnosis and treatment have prolonged overall survival (OS) for patients with breast cancer, metastasis remains the major obstacles to improved survival for breast cancer patients. The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence. Therefore, understanding the molecular pathways sustaining BCSC properties and targeting BCSCs will ultimately improve breast cancer treatments. In this study, we found that activation of ß-Catenin directly regulated CCL2 expression at the transcriptional level, and in turn promoted macrophages infiltration and M2 polarization. Moreover, macrophages co-cultured with breast cancer cells showed a significant increase in CCL2 expression and promoted ß-Catenin-induced BCSCs properties, whereas depletion of CCL2 by adding neutralizing antibodies suppressed BSCSs properties. In addition, we found that ß-Catenin-mediated CCL2 secretion recruited macrophages into tumor microenvironment and promoted breast cancer growth and metastasis in vivo. Clinically, we observed a significant positive correlation between ß-Catenin, CCL2 and CD163 expression, and increased expression of ß-Catenin, CCL2 and CD163 predicted poor prognosis in breast cancer. Furthermore, pharmacological inhibition of CCR2 and ß-Catenin synergistically suppressed BCSC properties and breast cancer growth. Collectively, our findings suggested that ß-Catenin-mediated CCL2 secretion forms a paracrine feedback loop between breast cancer cells and macrophages, which in turn promotes BCSC properties and supports breast cancer growth and metastasis. Targeting ß-Catenin/CCL2 signaling might be an effective strategy for breast cancer therapy.

Integrative Analysis of DNA Methylation and Transcriptome Identifies a Predictive Epigenetic Signature Associated With Immune Infiltration in Gliomas.

Glioma is the most common primary brain tumor with poor prognosis and high mortality. The purpose of this study was to use the epigenetic signature to predict prognosis and evaluate the degree of immune infiltration in gliomas. We integrated gene expression profiles and DNA methylation data of lower-grade glioma and glioblastoma to explore epigenetic differences and associated differences in biological function. Cox regression and lasso analysis were used to develop an epigenetic signature based on eight DNA methylation sites to predict prognosis of glioma patients. Kaplan-Meier analysis showed that the overall survival time of high- and low-risk groups was significantly separated, and ROC analysis verified that the model had great predictive ability. In addition, we constructed a nomogram based on age, sex, 1p/19q status, glioma type, and risk score. The epigenetic signature was obviously associated with tumor purity, immune checkpoints, and tumor-immune infiltrating cells (CD8+ T cells, gamma delta T cells, M0 macrophages, M1 macrophages, M2 macrophages, activated NK cells, monocytes, and activated mast cells) and thus, it may find application as a guide for the evaluation of immune infiltration or in treatment decisions in immunotherapy.

FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis.

Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.

An efficient classification method based on principal component and sparse representation.

As an important application in optical imaging, palmprint recognition is interfered by many unfavorable factors. An effective fusion of blockwise bi-directional two-dimensional principal component analysis and grouping sparse classification is presented. The dimension reduction and normalizing are implemented by the blockwise bi-directional two-dimensional principal component analysis for palmprint images to extract feature matrixes, which are assembled into an overcomplete dictionary in sparse classification. A subspace orthogonal matching pursuit algorithm is designed to solve the grouping sparse representation. Finally, the classification result is gained by comparing the residual between testing and reconstructed images. Experiments are carried out on a palmprint database, and the results show that this method has better robustness against position and illumination changes of palmprint images, and can get higher rate of palmprint recognition.