BackgroundDysregulated miR-7 and aberrant NF-κB activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis.MethodsTCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-κB RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed.ResultsLow miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-κB transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-κB activator LPS obviously restored miR-7-suppressed NF-κB transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion.ConclusionsOur data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-κB activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-κB-driven GC distant metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1074-6) contains supplementary material, which is available to authorized users.

Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate the degradation of the rate-limiting cholesterol biosynthesis enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by endoplasmic reticulum (ER) membrane-associated protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here, we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO). To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation, we performed a small-scale shRNA-based screening targeting ER-localized E3s. We found that knockdown of both ring finger protein 145 (Rnf145) and gp78 genes abrogates sterol-induced degradation of HMGCR in CHO cells. We also observed that RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR.Moreover, the tetrapeptide sequence YLYF in the sterol-sensing domain and the C537 residue in the RING finger domain were essential for RNF145 binding to Insigs and RNF145 E3 activity, respectively.Of note, amino acid substitutions in the YLYF or of Cys-537 completely abolished RNF145-mediated HMGCR degradation. In summary, our study reveals that RNF145, along with gp78, promotes HMGCR degradation in response to elevated sterol levels and identifies residues essential for RNF145 function.

Background NRF2, a prime target of cellular defense against oxidative stress, has shown a dark side profile in cancer progression. GRIM-19, an essential subunit of the mitochondrial MRC complex I, was recently identified as a suppressive role in tumorigenesis of human gastric cancer (GC). However, little information is available on the role of GRIM-19 and its cross-talk with NRF2 in GC metastasis. Methods Online GC database was used to investigate DNA methylation and survival outcomes of GRIM-19. CRISPR/Cas9 lentivirus-mediated gene editing, metastasis mice models and pharmacological intervention were applied to investigate the role of GRIM-19 deficiency in GC metastasis. Quantitative RT-PCR, FACS, Western blot, IHC, IF and reporter gene assay were performed to explore underlying mechanisms. Results Low GRIM-19 is correlated with poor survival outcome of GC patients while DNA hypermethylation is associated with GRIM-19 downregulation. GRIM-19 deficiency facilitates GC metastasis and triggers aberrant oxidative stress as well as ROS-dependent NRF2-HO-1 activation. Experimental interventions of specific ROS, NRF2 or HO-1 inhibitor significantly abrogate GRIM-19 deficiency-driven GC metastasis in vitro and in vivo. Moreover, HO-1 inhibition not only reverses GRIM-19 deficiency-driven NRF2 activation, but also feedback blocks NRF2 activator-induced NRF2 signaling, resulting in decreased metastasis-associated genes. Conclusions Our data suggest that GRIM-19 deficiency accelerates GC metastasis through the oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into the role of oncogenic NRF2 in tumor progression, but also provides new strategies to alleviate the dark side of NRF2 by targeting HO-1.

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Background:The chronic unpredictable mild stress (CUMS) model has long been considered the best model for exploring the pathophysiological mechanisms underlying depression. However, there are no widely recognised standards for strategies for modeling and for behavioral testing. The present study aimed to optimize the protocols for food deprivation and the sucrose preference test (SPT) for the CUMS model. Methods:We first evaluated the effects of different long periods of food deprivation on the body weight of Sprague Dawley (SD) rats by testing food deprivation for 24 hours (8:00-8:00 + ), food deprivation for 12 hours during the daytime (8:00-20:00) and food deprivation for 12 hours at night (20:00-8:00 + ). Next, we established a SD rat CUMS model with 15 different stimulations, and used body weight measurement, SPT, forced swim test (FST), open field test (OFT) and Morris water maze (MWM) test to verify the success of the modeling. In the SPT, consumption of sucrose and pure water within 1 and 12 hours was measured.Results: Twelve hours of food deprivation during the daytime (8:00-20:00) had no effect on body weight, while 12 hours of food deprivation at night (20:00-8:00 + ) and 24 hours of food deprivation (8:00-8:00 + ) significantly reduced the mean body weight of the SD rats. When SPT was used to verify the successful establishment of the CUMS rat model, sucrose consumption measured within 12 hours was less variable than that measured within 1 hour. Conclusions:Twelve hours of food deprivation in the daytime (8:00-20:00) may be considered a mild stimulus for the establishment of a CUMS rat model. Measuring sucrose consumption over 12 hours is recommended for SPT. K E Y W O R D S chronic unpredictable mild stress, forced swim test, Morris water maze, open field test, sucrose preference test, weight body

Background: Dengue has become one of the major vector-borne diseases, which has been an important public health concern. We aimed to estimate the disease burden of dengue in major endemic regions from 1990 to 2019, and explore the impact pattern of the socioeconomic factors on the burden of dengue based on the global burden of diseases, injuries, and risk factors study 2019 (GBD 2019). Methods: Using the analytical strategies and data from the GBD 2019, we described the incidence and disability-adjusted life years (DALYs) of dengue in major endemic regions from 1990 to 2019. Furthermore, we estimated the correlation between dengue burden and socioeconomic factors, and then established an autoregressive integrated moving average (ARIMA) model to predict the epidemic trends of dengue in endemic regions. All estimates were proposed as numbers and age-standardized rates (ASR) per 100,000 population, with uncertainty intervals (UIs). The ASRs of dengue incidence were compared geographically and five regions were stratified by a sociodemographic index (SDI). Results: A significant rise was observed on a global scale between 1990 and 2019, with the overall age-standardized rate (ASR) increasing from 557.15 (95% UI 243.32–1212.53) per 100,000 in 1990 to 740.4 (95% UI 478.2–1323.1) per 100,000 in 2019. In 2019, the Oceania region had the highest age-standardized incidence rates per 100,000 population (3173.48 (95% UI 762.33–6161.18)), followed by the South Asia region (1740.79 (95% UI 660.93–4287.12)), and then the Southeast Asia region (1153.57 (95% UI 1049.49–1281.59)). In Oceania, South Asia, and Southeast Asia, increase trends were found in the burden of dengue fever measured by ASRs of DALY which were consistent with ASRs of dengue incidence at the national level. Most of the countries with the heaviest burden of dengue fever occurred in areas with low and medium SDI regions. However, the burden in high-middle and high-SDI countries is relatively low, especially the Solomon Islands and Tonga in Oceania, the Maldives in South Asia and Indonesia in Southeast Asia. The age distribution results of the incidence rate and disease burden of dengue fever of major endemic regions showed that the higher risk and disease burden are mainly concentrated in people under 14 or over 70 years old. The prediction by ARIMA showed that the risk of dengue fever in South and Southeast Asia is on the rise, and further prevention and control is warranted. Conclusions: In view of the rapid population growth and urbanization in many dengue-endemic countries, our research results are of great significance for presenting the future trend in dengue fever. It is recommended to policy makers that specific attention needs to be paid to the negative impact of urbanization on dengue incidence and allocate more resources to the low-SDI areas and people under 14 or over 70 years old to reduce the burden of dengue fever.

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