Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-κB/Slug pathway.

Hepatocellular carcinomas are an aggressive malignancy mainly due to metastasis or postsurgical recurrence. Expression of E-cadherin is strongly reduced in Hepatocellular carcinoma (HCC) tissues, and its downregulation is connected to invasiveness and metastasis in hepatocellular carcinomas. The previous study showed that the supernatant from activated macrophages can downregulate the expression of E-cadherin in HCC cells. The partial known molecular mechanism is that tyrosine kinases c-Src- and EGFR phosphorylate ß-catenin and E-cadherin leading to destabilization of E-cadherin/ß-catenin complex. The aim of this study is to clarify other mechanism by which activated macrophages downregulate the expression of E-cadherin. We detect the expression of E-cadherin and macrophage infiltration in hepatocellular carcinoma tissues by double-staining immunohistochemistry and evaluate the relationship between macrophages and E-cadherin expression in hepatocellular carcinoma cells in vitro experiments. We found that reduced expression of E-cadherin was associated with macrophage infiltration along the border between the tumor nest and stroma in hepatocellular carcinoma tissues. Besides, protein expression of E-cadherin was significantly decreased in hepatocellular carcinoma cells co-cultured with macrophages derived from THP-1 cells. Consistently, mRNA expression of E-cadherin was also decreased in cancer cells co-cultured with THP-1-differentiated macrophages. Moreover, the downregulation of E-cadherin expression was companied by upregulation of Slug expression in cancer cells with conditional medium from THP-1-differentiated macrophage culture. The change in expression of E-cadherin and Slug was abrogated when NF-κB signaling pathway was blocked. All the findings suggested that macrophages contributed to the decreased expression of E-cadherin by NF-κB/Slug pathway in hepatocellular carcinomas.

FAK-LINC01089 negative regulatory loop controls chemoresistance and progression of small cell lung cancer.

The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.

The c-Src/LIST Positive Feedback Loop Sustains Tumor Progression and Chemoresistance.

Chemotherapy resistance and treatment failure hinder clinical cancer treatment. Src, the first mammalian proto-oncogene to be discovered, is a valuable anti-cancer therapeutic target. Although several c-Src inhibitors have reached the clinical stage, drug resistance remains a challenge during treatment. Herein, a positive feedback loop between a previously uncharacterized long non-coding RNA (lncRNA), which the authors renamed lncRNA-inducing c-Src tumor-promoting function (LIST), and c-Src is uncovered. LIST directly binds to and regulates the Y530 phosphorylation activity of c-Src. As a c-Src agonist, LIST promotes tumor chemoresistance and progression in vitro and in vivo in multiple cancer types. c-Src can positively regulate LIST transcription by activating the NF-κB signaling pathway and then recruiting the P65 transcription factor to the LIST promoter. Interestingly, the LIST/c-Src interaction is associated with evolutionary new variations of c-Src. It is proposed that the human-specific LIST/c-Src axis renders an extra layer of control over c-Src activity. Additionally, the LIST/c-Src axis is of high physiological relevance in cancer and may be a valuable prognostic biomarker and potential therapeutic target.

The schizophrenia and gut microbiota: A bibliometric and visual analysis.

Background: Many studies have explored the link between the gut microbiota and schizophrenia. To date, there have been no bibliometric analyses to summarize the association between the gut microbiota and schizophrenia. We aimed to conduct a bibliometric study of this association to determine the current status and areas for advancement in this field. Materials and methods: Publications related to the gut microbiota and schizophrenia were retrieved from the Web of Science Core Collection (WoSCC). The WoSCC literature analysis wire and VOSviewer 1.6.16 were used to conduct the analysis. Results: In total, 162 publications were included in our study. The publications generally showed an upward trend from 2014. A total of 873 authors from 355 organizations and 40 countries/regions contributed to this field. The leading authors were Timothy Dinan, John F Cryan, and Emily Severance. The leading institutions were Johns Hopkins University, the University College Cork, and the University of Toronto. The most productive countries were the United States (US), China, and Canada. In total, 95 journals contributed to this field. Among them, the top three productive journals were Schizophrenia Research, Progress in Neuro Psychopharmacology Biological Psychiatry, and Frontiers in Psychiatry. The important keywords in the clusters were gut microbiome, bipolar disorder, schizophrenia, antipsychotics, weight gain, metabolic syndrome, gut-brain axis, autism, depression, inflammation, and brain. Conclusion: The main research hotspots involving the connection between schizophrenia and the gut microbiota were the characteristics of the microbiota composition in schizophrenia patients, the gut-brain axis, and microbial-based interventions for schizophrenia. The studies about the association between gut microbiota and schizophrenia are limited, and more studies are needed to provide new insights into the gut microbiota in the pathogenesis and treatment of schizophrenia.

Mutual dependency between lncRNA LETN and protein NPM1 in controlling the nucleolar structure and functions sustaining cell proliferation.

Fundamental processes such as ribosomal RNA synthesis and chromatin remodeling take place in the nucleolus, which is hyperactive in fast-proliferating cells. The sophisticated regulatory mechanism underlying the dynamic nucleolar structure and functions is yet to be fully explored. The present study uncovers the mutual functional dependency between a previously uncharacterized human long non-coding RNA, which we renamed LETN, and a key nucleolar protein, NPM1. Specifically, being upregulated in multiple types of cancer, LETN resides in the nucleolus via direct binding with NPM1. LETN plays a critical role in facilitating the formation of NPM1 pentamers, which are essential building blocks of the nucleolar granular component and control the nucleolar functions. Repression of LETN or NPM1 led to similar and profound changes of the nucleolar morphology and arrest of the nucleolar functions, which led to proliferation inhibition of human cancer cells and neural progenitor cells. Interestingly, this inter-dependency between LETN and NPM1 is associated with the evolutionarily new variations of NPM1 and the coincidental emergence of LETN in higher primates. We propose that this human-specific protein-lncRNA axis renders an additional yet critical layer of regulation with high physiological relevance in both cancerous and normal developmental processes that require hyperactive nucleoli.

Oncogenic Properties of NEAT1 in Prostate Cancer Cells Depend on the CDC5L-AGRN Transcriptional Regulation Circuit.

The long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been shown to regulate multiple cancer-related cellular activities including cell proliferation, apoptosis, and migration. In this study, we confirm that repression of NEAT1 induces DNA damage, disturbs the cell cycle, and arrests the proliferation of prostate cancer cells. By taking advantage of the prostate cancer tumor transcriptome profiles from The Cancer Genome Atlas, our data-mining pipeline identified a series of transcription factors (TF) whose regulatory activities on target genes depended on the level of NEAT1. Among them was putative TF CDC5L, which bound directly to NEAT1. Silencing NEAT1 in prostate cancer cells repressed the transcriptional activity of CDC5L, and RNA-seq and ChIP-seq analyses further revealed a handful of potential targets of CDC5L regulated by NEAT1 expression. One target of CDC5L, ARGN, mediated the strong phenotypic consequences of NEAT1 reduction, including DNA damage, cell-cycle dysregulation, and proliferation arrest. In summary, we have established the requirement of the CDC5L-AGRN circuit for the essential oncogenic role of NEAT1 in prostate cancer cells.Significance: An integrative methodology uncovers CDC5L-AGRN signaling as critical to the tumor-promoting function of long noncoding RNA NEAT1 in prostate cancer cells. Cancer Res; 78(15); 4138-49. ©2018 AACR.

A20 inhibits the motility of HCC cells induced by TNF-α.

Metastasis of hepatocellular carcinoma (HCC) can be facilitated by TNF-α, a prototypical inflammatory cytokine in the HCC microenvironment. A20 is a negative regulator of NF-κB signaling pathway. In the present study we ask whether A20 plays a role in HCC metastasis. We found that A20 expression was downregulated in the invasive cells of microvascular invasions (MVI) compared with the noninvasive cells in 89 tissue samples from patients with HCC by immunochemistry methods. Overexpression of A20 in HCC cell lines inhibited their motility induced by TNF-α. Furthermore, the overexpression of A20 inhibited epithelial-mesenchymal transition (EMT), FAK activation and RAC1 activity. By contrast, knockdown of A20 in one HCC cell line results in the converse. In addition, the overexpression of A20 restrained the formation of MVI in HCC xenograft in nude mice treated with TNF-α. All the results suggested that A20 functioned as a negative regulator in motility of HCC cells induced by TNF-α.

CD68(+)HLA-DR(+) M1-like macrophages promote motility of HCC cells via NF-κB/FAK pathway.

TAM is a prominent component of inflammatory microenvironment, presenting M1 and M2 polarized states in HCC. The objective of this study is to investigate the relationship between M1-polarized macrophages and metastasis in HCC. We used immunohistochemical double-staining method to inspect the infiltration of CD68(+)HLA-DR(+) M1-like macrophages in HCC tissues. The M1-polarized macrophage was derived from THP-1 cell treated by LPS and IFN-γ in vitro. Transwell migration assay was used to evaluate whether the M1-polarized macrophage enhanced motility of HCC cells in the presence or absence of NF-κB inhibitor Bay 11-7802. The activation of NF-κB and FAK signaling pathways was examined by Western blot assay. Our results showed that the density of CD68(+)HLA-DR(+) TAM in the HCC with metastasis is significantly higher than that in the HCC without metastasis. Moreover, the conditioned medium from the M1 macrophages promote the migration of HCC cells and induced the activation of NF-κB and FAK signaling. The promoted migration of HCC cells was abrogated by the Bay 11-7802, as well as the activation of NF-κB and FAK pathway. Our findings implied a pro-metastatic role of M1-like TAM in HCC.