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Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) have been considered as biomarkers or regulators in many diseases. However, the exact role of circRNA- or lncRNA-mediated competing endogenous RNA (ceRNA) networks in the modulation of depression pathogenesis-relevant processes is not clear. In this study, we profiled whole transcriptome in depression patients' blood samples via microarray analysis. As a result, a total of 340 circRNAs, 398 lncRNAs, 206 miRNAs, and 92 mRNAs were differentially expressed between the depression and control groups. Then, we constructed ceRNA networks according to the differentially expressed genes (DEGs). Using bioinformatics analysis, 89 pairs of circRNA-ceRNA and 49 pairs of lncRNA-ceRNA networks were obtained. Since depression is a broad and heterogeneous condition that is known as promoter for many chronic diseases including cancer, so we further dug out 28 circRNAs, 61 lncRNAs, 26 miRNAs, and 29 mRNAs that are associated with cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the DEGs were significantly enriched in cancer-related signaling pathways such as MAPK, Wnt, IL-17, Ras, and PI3K-Akt. Genes involved in the above pathways such as S100A9, GATA2, SRFP5, SLC45A3, NTRK1, FRZB, has_circ_0014221, has_circ_0014220, and has_circ_0087100 were dysregulated in various cancer cell lines by stress hormones induced. HDC, GATA2, SLC45A3, and NTRK1 were downregulated in tumor-bearing mice subjected to chronic unpredictable mild stress (CUMS). LncRNA-mediated ceRNA network validation showed that overexpression of miR-4530 declined HDC level. Our findings highlight the potential circRNA- and lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of depression and as potential biomarkers in depression cancer comorbidity through the pathways of IL-17 or histidine metabolism. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence, and therapeutic resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying HCC CSC regulation remain largely unknown. Here we report our analysis of 97 paraffin-embedded HCC tumor specimens. We found that protein tyrosine kinase 2 (PTK2) expression correlated with liver CSC marker expression, overall survival, and recurrence-free survival in HCC patients. Our results further showed that PTK2 activated Wnt/β-catenin signaling by promoting nuclear accumulation of β-catenin in HCC cells. In this manner, PTK2 activates CSC traits and drives tumorigenicity in HCC cells, leading to HCC recurrence and sorafenib resistance. Moreover, PTK2 expression was negatively correlated with its level of promoter methylation. PTK2 apparently acts as an oncogene by increasing CSC traits and tumorigenicity in HCC. The present data suggest that PTK2 may be a novel prognostic biomarker for HCC recurrence, and a therapeutic target for HCC treatment. [ABSTRACT FROM AUTHOR]

Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3β activation, Wnt/β-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3β-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-β and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic. [ABSTRACT FROM AUTHOR]

Microvesicles (MVs) secreted from cells have been found to mediate signal transduction between cells. In the tumor microenvironment, VEGF released from cancer cells plays a key role in promoting tumor angiogenesis. In this study, we characterized the inhibitory effect of MV-delivered miR-29a/c on angiogenesis and tumor growth in gastric cancer (GC). We found that the downregulation of miR-29a/c increases VEGF expression and release in GC cells, promoting the growth of vascular cells. By simulating the tumor microenvironment, the MV-delivered miR-29a/c significantly suppresses VEGF expression in GC cells, inhibiting vascular cell growth, metastasis, and tube formation. We also used a tumor implantation mouse model to show that secreted MVs containing overexpressed miR-29a/c significantly reduced the growth rate of the vasculature and tumors in vivo. To conclude, our results contribute to a novel anti-cancer strategy using miRNA-containing MVs to control tumor cell growth by blocking angiogenesis. [ABSTRACT FROM AUTHOR]

Growth cone collapse is a critical repulsive response to various guidance cues for axon guidance. Protein kinase C epsilon (PKCε) plays important regulation roles in such responses. Translocation of PKCε from cytoplasm to membrane is crucial to archive its regulatory roles in this process. We previously reported that PDLIM5 could selectively recruit PKCε to its specific substrate in neurons. However, the molecular mechanism of PKCε translocation in the neuronal growth cone collapse remains elusive. Here, we demonstrated that PDLIM5 and PKCε co-existed in the nerve growth cones. By interacting with α-actinin, but not β-actin or β-tubulin, PDLIM5 might contribute to regulation of remodeling of the microfilaments in neurons. Meanwhile, PDLIM5 could also bind to PKCε to form PDLIM5-PKCε complexes in growth cones. In the primary cultured neurons, activation of PKCε by PMA resulted in translocation of both PKCε and PDLIM5 from cytoplasm to the membrane. Knockdown of either PDLIM5 or PKCε rescued the neuron from PMA-induced growth cone collapse. Furthermore, in neurons, application of PDLIM5 shRNA or over-expression of PDLIM5 LIM1-3 mutants reduced the amount of PKCε in the membrane. Together, these results suggest that PDLIM5 acts as a scaffold protein by mediated PKCε translocated to the membrane in PMA-induced growth cone collapse. [ABSTRACT FROM AUTHOR]

Enzalutamide, a novel androgen receptor (AR) antagonist, prolongs overall survival of patients with castration-resistant prostate cancer (CRPC); however, patients eventually progress with enzalutamide resistance. We studied the efficacy of sorafenib combined with enzalutamide in a CRPC model and explored a potential strategy to improve enzalutamide efficacy in vitro and in LNCaP xenografts. The results indicated that enzalutamide combined with sorafenib potently decreased cell proliferation and induced apoptosis in the prostate cancer cell lineLNCaP. In castrate-resistant LNCaP xenografts, the combination of enzalutamide with sorafenib significantly suppressed tumor growth compared with eachsingle agent. Western blots and immunohistochemical staining assay showed that the expression of AR was down-regulated, and the extracellular signal-regulated kinase (ERK) signaling pathway was inhibited after combination treatment, suggesting a synergistic inhibitory effect on the AR and ERK pathways. These results demonstrated that sorafenib therapy improved the efficacy of enzalutamide in the CRPC model, indicating a promising therapeutic strategy for clinical CRPC patients. [ABSTRACT FROM AUTHOR]