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Chronic inflammation is known to promote carcinogenesis; Dicer heterozygous mice are more likely to develop colitis-associated tumors. This study investigates whether Dicer is downregulated in inflamed colon tissues before malignancy occurs and whether increasing Dicer expression in inflamed colon tissues can alleviate colitis and prevent colitis-associated tumorigenesis. Methods: Gene expression in colon tissues was analyzed by immunohistochemistry, immunoblots, and real-time RT-PCR. Hydrogen peroxide or N-acetyl-L-cysteine was used to induce or alleviate oxidative stress, respectively. Mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors. Berberine, anastrozole, or pranoprofen was used to rescue Dicer expression in inflammatory colon tissues. Results: Oxidative stress repressed Dicer expression in inflamed colon tissues by inducing miR-215 expression. Decreased Dicer expression increased DNA damage and cytosolic DNA and promoted interleukin-6 expression upon hydrogen peroxide treatment. Dicer overexpression in inflamed colon tissues alleviated inflammation and repressed colitis-associated carcinogenesis. Furthermore, we found that anastrozole, berberine, and pranoprofen could promote Dicer expression and protect cells from hydrogen peroxide-induced DNA damage, thereby reducing cytosolic DNA and partially repressing interleukin-6 expression upon hydrogen peroxide treatment. Rescuing Dicer expression using anastrozole, berberine, or pranoprofen in inflamed colon tissues alleviated colitis and prevented colitis-associated tumorigenesis. Conclusions: Dicer was downregulated in inflamed colon tissues before malignancy occurred. Decreased Dicer expression further exaggerated inflammation, which may promote carcinogenesis. Anastrozole, berberine, and pranoprofen alleviated colitis and colitis-associated tumorigenesis by promoting Dicer expression. Our study provides insight into potential colitis treatment and colitis-associated colon cancer prevention strategies.

Statistics show that the prognosis of cervical cancer (CC) is poor, and the death rate of CC in advanced stage has been rising in recent years. Increasing evidence has demonstrated that circular RNAs (circRNAs) serve as promising biomarkers in human cancers, including CC. The present study planned to find out the circRNA involved in CC and to explore its regulatory mechanism in CC. We discovered the new circRNA, circ-0033550, upregulated in CC. Its associated gene was AKT (also known as protein kinase B) serine/threonine kinase 1 (AKT1), so we renamed circ-0033550 as circ-AKT1. We confirmed the high expression of circ-AKT1 in CC samples and cell lines, as well as the circle structure of circ-AKT1. Functionally, gain- and loss-of-function experiments indicated that circ-AKT1 and AKT1 promoted CC cell proliferation and invasion. Moreover, circ-AKT1 and AKT1 were induced by transforming growth factor beta (TGF-β) and facilitated EMT (epithelial-mesenchymal transition) in CC. Mechanically, we illustrated that circ-AKT1 upregulated AKT1 by sponging miR-942-5p. Rescue assays confirmed the role of the circ-AKT1/miR-942-5p/AKT1 axis in CC progression. In vivo assays validated that circ-AKT1 promoted tumor growth in CC. Overall, circRNA-AKT1 sequestered miR-942-5p to upregulate AKT1 and promote CC progression, which may offer a new molecular target for the treatment improvement of CC.

Cervical cancer is acknowledged as the most prevalent gynecological tumor and a severe public issue that threatens female health, resulting from its high incidence and fatality rate. Surging evidence have shown that circular RNAs (circRNAs) play significant roles in the initiation and progression of various malignancies. Although circAMOTL1 has been testified to execute oncogenic properties in breast cancer and prostate cancer, literature on its function and regulatory mechanism in cervical cancer development is still scanty. Using a bioinformatics analysis, we found circ_0004214 was a circular form of AMOTL1. Through qRT-PCR analysis, circAMOTL1 and its host gene AMOTL1 were both upregulated in cervical cancer tissues and closely correlated with poor prognosis of cervical cancer. Gain- or loss-of-function assays and in vivo experiments demonstrated that AMOTL1 promoted cervical cancer cell growth both in vitro and in vivo. Mechanically, circAMOTL1 served as a competing endogenous RNA (ceRNA) to prompt the expression of AMOTL1 through sponging miR-485-5p. Rescue assays revealed that miR-485-5p/AMOTL1 axis was involved in circ_AMOTL1-mediated cervical cancer progression. Our findings provide a better understanding of the molecular mechanism underlying circAMOTL1 in cervical cancer and indicated circAMOTL1/miR-485-5p/AMOTL1 as a promising novel therapeutic strategy for the treatment of this disease.

Background Cervical cancer is the second most common malignant cancer in women worldwide. Evidence indicated that miR-664 was significantly downregulated in cervical cancer. However, the mechanisms by which miR-664 regulates the tumorigenesis of cervical cancer remain unclear. Thus, this study aimed to investigate the role of miR-664 in cervical cancer. Methods Quantitative reverse transcription polymerase chain reaction was used to detect the level of miR-664 in tumor tissues and cell line. The dual luciferase reporter system assay and Western blotting were used to explore the interaction of miR-664 and c-Kit in cervical cancer. Results The expression of miR-664 in patients with cervical cancer was dramatically decreased compared with that in adjacent tissues. MiR-664 mimics significantly inhibited proliferation in SiHa cells via inducing apoptosis. In addition, miR-664 mimics induced apoptosis in SiHa cells via increasing the expressions of Bax and active caspase 3 and decreasing the level of Bcl-2. Moreover, dual-luciferase assay showed that c-Kit was the directly binding target of miR-664 in SiHa cells; overexpression of miR-664 downregulated the expression of c-Kit. Meanwhile, upregulation of miR-664 significantly decreased the levels of c-Myc and Cyclin D in cells. Furthermore, miR-664 markedly inhibited tumor growth of cervical cancer in xenograft. Conclusion Our data indicated that miR-664 exerted antitumor effects on SiHa cells by directly targeting c-Kit in vitro and in vivo. Therefore, miR-664 might be a potential therapeutic target for the treatment of patients with cervical cancer.

Tryptophan 2,3‑dioxygenase (TDO2) is a key rate‑limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription‑quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype‑Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12‑mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.

Human papillomaviruses 16 (HPV16) is the primary causative agent of cervical cancer (CC). E6 oncoprotein plays a crucial role in cervical carcinogenesis and commonly cause the dysregulation of the long noncoding RNAs (lncRNAs) expression. However, the biological function of lncRNAs in HPV16-related CC remains largely unexplored. In the present study HPV16 E6-induced differential expression of lncRNAs, miRNA, and mRNA were identified using microarray-based analysis and verified in tumor r cell lines and tumor tissues, and the function of lncRNA in CC was investigated in vitro and in vivo. We found that an lncRNA, named GABPB1-AS1, was significantly upregulated in HPV16-positive CC tissues and cell lines. GABPB1-AS1 expression in HPV16-positive CC tissues was positively associated with tumor size, lymph node metastasis, and FIGO stage. High expression of GABPB1-AS1 was correlated with a poor prognosis for HPV16-positive CC patients. Functionally, E6-induced GABPB1-AS1 overexpression facilitated CC cells proliferation and invasion in vitro and in vivo. Mechanistically, GABPB1-AS1 acted as a competing endogenous RNA (ceRNA) by sponging miR-519e-5p, resulting in the de-repression of its target gene Notch2 which is well known as an oncogene. Therefore, GABPB1-AS1 functioned as a tumor activator in CC pathogenesis by binding to miR-519e-5p and destroying its tumor suppressive function. Collectively, current results demonstrate that GABPB1-AS1 is associated with CC progression, and may be a promising biomarker or target for the clinical management of CC.

MicroRNA-34a (miR-34a) behaves as a tumor suppressor by decreasing the expression of oncogenes involved in multiple carcinogenic pathways. Intravenous delivery of miR-34a mimics has been investigated in clinical trials as a potential treatment for advanced cancers; however, the effect of miR-34a on cancer immune surveillance is controversial. In the current study, we found that miR-34a plays a dual role in the regulation of major histocompatibility complex class I-related sequence B (MICB) protein, a ligand of the NKG2D receptor. MiR-34a could both induce and reduce MICB expression by upregulating ataxia telangiectasia and Rad3-related (ATR) protein kinase and downregulating the transcription factor E2F1, respectively. The net effect of miR-34a on MICB expression depended on endogenous E2F1 levels. Overexpression of miR-34a promoted MICB expression in hepatocytes and hepatocellular carcinoma (HCC) cells that have low E2F1 levels but not in HCC cells that have high E2F1 levels. In HCC patients, the expression of miR-34a and MICB showed positive correlation in paratumor liver tissues, which have low E2F1 levels, but not in HCC tissues, which have high E2F1 levels. We showed that miR-34a overexpression in non-transformed liver cells enhanced cytolysis and interferon-γ production by NK-92MI cells. Furthermore, higher miR-34a expression in tumor and paratumor tissues was associated with positive and negative outcomes, respectively, in HCC patients. Our findings suggest that miR-34a induces MICB expression in paratumor liver tissues, which may cause liver damage and serious cytokine release syndrome, thus disclosing potential side effects of systemic administration of miR-34a in anticancer therapy.

Background Human papillomavirus (HPV) infection and viral proteins expression cause a number of epigenetic alterations leading to cervical carcinogenesis. The recent discovery of a large amount of histone methylation modifiers reveals important roles of these enzymes in regulating tumor progression. Methods The changes in expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E7 in CaSki cells. Lysine-specific demethylase 2A (KDM2A)-regulated microRNAs (miRNAs) in cervical cancer pathogenesis were disclosed using quantitative real-time polymerase chain reaction. The function of KDM2A-miRNAs on cervical cancer was investigated in vitro and in vivo. Results Upregulation of KDM2A induced by HPV16 E7 promotes cervical cancer cell proliferation and invasion and is correlated with poor prognosis in patients with cervical cancer. KDM2A physically interacts with the promoter of miR-132 and suppresses its expression by removing the mono or dimethyl group from H3K36 at the miR-132 locus. Functionally, miR-132 represses cancer cell proliferation and invasion by inhibiting radixin (RDX). Upregulated KDM2A promotes cervical cancer progression by repressing miR-132, which results in a derepression of RDX. Therefore, KDM2A functions as a tumor activator in cervical cancer pathogenesis by binding miR-132 promoter and abrogating its tumor suppressive function. Conclusion Our results suggest a function for KDM2A in cervical cancer progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of cervical cancer.

Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumors; however, the mechanisms responsible for DR-mediated antitumor effects have not been unequivocally identified. Here, we report that DR suppresses xenograft tumor growth by upregulating a novel signaling pathway. DR led to upregulated aldolase A (ALDOA) expression in xenograft tumors. ALDOA physically interacted with the catalytic subunit of DNA-dependent protein kinase (DNA-PK) and promoted DNA-PK activation. Activated DNA-PK phosphorylated p53 and increased its activity. Although ALDOA can function as an oncogene in cultured cells, it can also activate the tumor suppressor p53. Thus, ALDOA overexpression in the presence of p53 suppressed xenograft tumor growth; however, when p53 was suppressed, ALDOA overexpression promoted xenograft tumor growth. Moreover, we demonstrated that p53 suppression inhibited the antitumor effects of DR. Our results indicate that upregulation of the ALDOA/DNA-PK/p53 pathway is a mechanism accounting for the antitumor effects of DR.

To explore the complex molecular mechanisms of bladder cancer, mRNA and miRNA expression profiles were combined for systematic analyses. A total of 18 common differentially expressed genes (DEGs) were identified from two mRNA expression datasets which consisted of 206 tumor and 74 normal tissues. Then, survival analysis based on the SurvExpress database showed that the common DEGs were able to significantly differentiate low- and high-risk groups in 4 public bladder cancer datasets (p

The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

Background We are committed to investigate miR-218-5 effects on the progression of cervical cancer (CC) cell and find out the molecular mechanism. Methods GSE9750 was obtained from GEO database and R Limma package was applied to filter out dysregulated genes. The pathways were enriched by GSEA software, ClusterProfiler and enrichplot packages to predict the function of DEGs. The binding sites of LYN were detected by miRanda and TargetScan. The miR2Disease database was used to find miRNAs related with CC. The expression of miR-218-5p and LYN were quantified by qRT-PCR and that of LYN protein was measured by western blot. The targeted relationships between miR-218-5p and LYN were verified by dual-luciferase reporter assay. Colony formation assays, wound healing, transwell invasion assay and flow cytometer analysis were performed to investigate the roles that miR-218-5p and LYN played in migration, invasion and death of cervical carcinoma. Xenografts established in nude mice were used to assess tumor growth in vivo. Results The highly expressed mRNA LYN was selected by microarray analysis in GSE9750. NF-κB signaling pathway was enriched base on GSEA results. The expression of miR-218-5p was lower but LYN was higher in CC primary tumors compared with normal control. In addition, miR-218-5p could regulate the expression of LYN in HeLa cells negatively. Overexpression of LYN could promote cell migration and invasion, but inhibit cell death in vitro, and also promote tumor formation in vivo via activating NF-κB signaling pathway which could be reversed by miR-218-5p. Conclusions MiR-218-5p suppressed the progression of CC via LYN/NF-κB signaling pathway.

Human papillomavirus (HPV) infection and viral protein expression cause several epigenetic alterations that lead to cervical carcinogenesis. Our previous study identified that upregulated lysine-specific demethylase (KDM) 2 A promotes cervical cancer progression by inhibiting mircoRNA (miR)-132 function. However, the roles of histone methylation modifiers in HPV-related cervical cancer remain unclear. In the present study, changes in the expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E6/E7 in CaSki cells. The dysregulated expression of KDM5A was identified, and its function in cervical cancer was investigated in vitro and in vivo. E7 oncoprotein-induced upregulation of KDM5A promoted cervical cancer cell proliferation and invasiveness in vitro and in vivo, which was correlated with poor prognosis in patients with cervical cancer. KDM5A was found to physically interact with the promoter region of miR-424–5p, and to suppress its expression by removing the tri- and di-methyl groups from H3K4 at the miR-424–5p locus. Furthermore, miR-424–5p repressed cancer cell proliferation and invasiveness by targeting suppressor of zeste 12 (Suz12). KDM5A upregulation promoted cervical cancer progression by repressing miR-424–5p, which resulted in a decrease in Suz12. Therefore, KDM5A functions as a tumor activator in cervical cancer pathogenesis by binding to the miR-424–5p promoter and inhibiting its tumor-suppressive function. These results indicate a function for KDM5A in cervical cancer progression and suggest its candidacy as a novel prognostic biomarker and target for the clinical management of this malignancy.

The present study investigated the underlying regulatory network involved in the differential expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) long non‑coding (lnc)RNA, microRNA‑17‑5p (miR‑17‑5p) and frizzled class receptor 2 (FZD2) mRNA under the influence of Casiopeina II‑gly (Cas‑II‑gly) via the Wnt signaling pathway in cervical carcinoma (CC). The gene expression data were obtained from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/), and the differentially expressed genes were determined using R software. The R ClusterProfiler and enrichplot packages were applied for gene‑set enrichment analysis based on the Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes databases. TargetScan and the starBase database were used to predict the targeting associations between the miRNAs and lncRNAs/mRNAs. The MALAT1/miR‑17‑5p/mRNA FZD2 expression levels were measured via reverse transcription‑quantitative polymerase chain reaction. The protein expression was monitored by western blot analysis. The target association among the lncRNA MALAT1, miR‑17‑5p and FZD2 was validated via a dual luciferase reporter assay. Cell viability and apoptosis were determined via MTT assays, EdU staining and flow cytometry. The results indicated that the expression levels of lncRNA MALAT1 and FZD2 mRNA were downregulated, while miR‑17‑5p expression was upregulated in HeLa and CaSki cells treated with increasing Cas‑II‑gly concentrations. The cell viability was decreased, and the apoptosis rate was increased in HeLa and CaSki cells following Cas‑II‑gly treatment. Furthermore, western blot analysis results demonstrated that Cas‑II‑gly and the MALAT1/miR‑17‑5p/FZD2 axis could affect the expression of proteins associated with the Wnt signaling pathway, including disheveled segment polarity protein, glycogen synthase kinase‑3β and β‑catenin, and via the MALAT1/miR‑17‑5p/FZD2/Wnt signaling pathway axis.

The molecular mechanisms of cervical cancer have been minimally explored with multi-omics data. In the present study, mRNA expression profiles were analyzed and combined with predicted miRNA interactions to contribute to the characterization of the underlying regulatory mechanisms of cervical cancer. A total of 92 significantly differentially expressed genes (DEGs) were identified in 33 tumor samples by comparison with 29 normal samples. mRNA-miRNA interaction network analysis revealed that 16 out of the 92 DEGs, including checkpoint kinase 1 (CHEK1), SRY-box 17 (SOX17), centrosomal protein 55, cyclin dependent kinase inhibitor 2A (CDKN2A), and inhibitor of DNA binding 4, were the targets of 4 miRNAs which were previously reported to be involved in the regulation of cervical cancer. Tumor and normal samples could be distinctly classified into two groups based on the expression of the 16 DEGs. Furthermore, survival analysis using the SurvExpress database indicated that the 16 DEGs could individually significantly differentiate low- and high-risk cervical cancer groups. Overall, multiple biological processes are likely to participate in the progression of cervical cancer based on the pathway and function enrichment identified for the DEGs. The dysregulation of SOX17 is associated with the regulation of embryonic development, the determination of cell fate and likely promotes cancer cell transformation. The dysregulation of CHEK1 and CDKN2A further promote cancer cell proliferation by affecting the cell cycle checkpoint in response to DNA damage. The identification of critical genes and biological processes associated with cervical cancer may be beneficial for the exploration of the molecular mechanisms.

OBJECTIVES Recently, thousands of long non-coding RNAs (lncRNAs) involved in development and metastasis of malignant tumors have been identified. Long non-coding RNA (lncRNA) breast cancer anti-estrogen resistance 4 (BCAR4) has been proved to promote proliferation and metastasis in multiple tumors. However, the function and significance of BCAR4 in cervical cancer are still unclear. METHODS In this study, we concentrated on the biological function and clinical significance of BCAR4 in cervical cancer. More specifically, BCAR4 expression was evaluated in cervical cancer tissues and cell lines by qRT-PCR. Moreover, the prognostic factors were assessed by Kaplan-Meier analysis and Cox proportional hazards models. Additionally, functional assays were conducted and the potential mechanism was explored. RESULTS Our study showed that BCAR4 expression was significantly up-regulated in cervical cancer tissue and cell lines. Moreover, patients with high BCAR4 expression showed worse survival outcomes and overexpression of BCAR4 might be an independent prognostic factor in cervical cancer. Furthermore, overexpression of BCAR4 remarkably promoted the proliferation, motility of cervical cancer cells and silencing BCAR4 significantly suppressed the proliferation, migration and invasion of cervical cancer cells. Additionally, overexpression of BCAR4 promoted epithelial-mesenchymal transition (EMT) process and silencing BCAR4 suppressed EMT process in cervical cancer cells. CONCLUSIONS The results indicated that BCAR4 might play a crucial role in cervical cancer progression and act as an underlying biomarker for the diagnosis and prognosis of cervical cancer.

Emerging evidence indicates that microRNAs play critical roles in carcinogenesis and cancer progression. In this study, miR-133a was found to be significantly downregulated in colon tumor tissues. We aimed to determine its biological function, molecular mechanisms, and direct target genes in colorectal cancer. From these results, we found that miR-133a was significantly downregulated in primary tumor tissues and colon cancer cell lines. Ectopic expression of miR-133a in colon cancer cell lines significantly suppressed cell growth, as evidenced by cell viability and colony formation assays, as well as reduced xenograft tumor growth in nude mice. However, the effect of miR-133a was abolished by the overexpression of eIF4A1. Moreover, miR-133a inhibited cellular migration and invasiveness. A luciferase activity assay revealed oncogene eukaryotic translation initiation factor 4A1 as a direct target gene of miR-133a, whose expression was inversely correlated with that of miR-133a. Our results demonstrate that miR-133a plays a pivotal role in colorectal cancer by inhibiting cell proliferation, invasion, and migration by targeting oncogenic eukaryotic translation initiation factor 4A1, which acts as a tumor suppressor and may provide a new potential therapeutic target in colorectal cancer.

Cervical cancer is the second most common gynecological cancer worldwide and remains as one of the leading causes of cancer-related death among women. Despite great progress in the treatment of cervical cancer, the 5-year overall survival rate for patients with this disease remains unsatisfactory. Over the past decade, an increasing number of studies indicate a central role for microRNAs in the initiation and progression of cervical cancer. microRNA‑329-3p (miR-329-3p) has been studied in many types of human cancer; however, the expression level, biological role and the underlying mechanism of miR-329-3p in cervical cancer has not yet been investigated. In the present study, we found that the expression levels of miR-329-3p were reduced in both cervical cancer tissues and cell lines. Low miR-329-3p expression was negatively correlated with histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis of cervical cancer patients. In addition, upregulation of miR‑329-3p suppressed cell proliferation, migration and invasion of cervical cancer. Furthermore, MAPK1 was identified as a direct target gene of miR-329-3p. MAPK1 was significantly upregulated in cervical cancer tissues and was inversely correlated with miR-329-3p expression in the cervical cancer tissues. Silencing of MAPK1 by RNA interference mimicked the effects of miR-329-3p overexpression on cell proliferation, migration and invasion in cervical cancer. Moreover, rescue experiments showed that restoration of the expression of MAPK1 reversed the effects of miR‑329-3p overexpression in cervical cancer cells. Taken together, these findings suggest that miR-329-3p has a critical tumor-suppressive roles by directly targeting MAPK1 in cervical cancer, and it may be investigated as a novel therapeutic target for the treatment of patients with this disease.

Non-alcoholic fatty liver disease is highly associated with morbidity and mortality in population. Although studies have already demonstrated that the immune response plays a pivotal role in the development of non-alcoholic fatty liver disease, the comprehensive regulation is unclear. Therefore, present study was carried out to investigate the non-alcoholic fatty liver disease development under neutrophil depletion. To achieve the aim of the study, C57BL/6 J mice were fed with high fat diet for 6 weeks before treated with neutrophil deplete antibody 1A8 or isotype control (200 μg/ mouse every week) for another 4 weeks. Treated with 1A8 antibody, obese mice exhibited better whole body metabolic parameters, including reduction of body weight gain and fasting blood glucose levels. Neutrophil depletion also effectively reduced hepatic structural disorders, dysfunction and lipid accumulation. Lipid β-oxidative markers, phosphorylated-AMP-activated protein kinase α and phosphorylated-acetyl-CoA carboxylase levels were increased in 1A8 antibody-treated obese mouse group. The mitochondrial number and function were also reversed after 1A8 antibody treatment, including increased mitochondrial number, reduced lipid oxidative damage and enhanced mitochondrial activity. Furthermore, the expression of inflammatory cytokines, tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were obviously reduced after neutrophil depletion, accompanied with decreased F4/80 mRNA level and macrophage percentage in liver. The decreased NF-κB signaling activity was also involved in the beneficial effect of neutrophil depletion. Taken together, neutrophil depletion could attenuate metabolic syndromes and hepatic dysfunction.

Objective Ovarian cancer is one of the most lethal of women cancers and lack potent therapeutic options. There have many evidences demonstrate the Notch signaling has deregulation in variety of human malignancies.MK-0752 is a novel potent γ-secretase inhibitor and now assessed in clinical trial for treatment of several types of cancer, our objective was to investigate the anticancer effects and mechanisms of MK-0752 alone or combined with cisplatin in ovarian cancer. Methods Cell lines used: A2780, OVCAR3, SKOV3, HO8910PM, the effects of MK-0752 and cisplatin on cell proliferation were measured by MTT assay. The effect of combination treatment was examined by isobologram analysis. The distribution of cell cycle and cell apoptosis were analyzed using PI and Annexin V-FITC/PI staining by flow cytometric analysis. The mechanism in biochemistry was analyzed by using Western blot. Mouse xenograft model of A2780 was established to observe the anti-ovarian cancer effects in vivo setting, nude mice were randomized into four groups (n=6 per group) and treated every 4days with control (solvent) group, MK-0752(25mg/kg) group, cisplatin (2mg/kg)group, combination group (both of MK-0752 and cisplatin). Results MK-0752 alone actively induced cell growth inhibition, G2/M phase cell cycle arrest and apoptosis with down-regulation of Notch1 and its downstream effectors including Hes1, XIAP, c-Myc and MDM2 in a dose- and time-dependent manner. Moreover, sequential combination of cisplatin prior to MK-0752 significantly promoted cell apoptosis and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Conclusion Our data supports the sequential combination of cisplatin prior to MK-0752 is a highly promising novel experimental therapeutic strategy against ovarian cancer.