Silencing of lncRNA DLEU1 inhibits tumorigenesis of ovarian cancer via regulating miR-429/TFAP2A axis.

Long non-coding RNAs (lncRNAs) are known as crucial regulators in the development of OC. In the current study, we aim to explore the function and molecular mechanism of lncRNA DLEU1 in OC. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to determine the expression of DLEU1, miR-429, and TFAP2A in OC cells and tissues. The relationship among DLEU1, miR-429, and TFAP2A was tested by dual-luciferase reporter (DLR) assay. Besides, the proliferative, migratory and invasive abilities of OC cells were analyzed by MTT, wound healing, and transwell assays, respectively. Western blot was performed to determine the protein expression of TFAP2A. The expression of lncRNA DLEU1 and TFAP2A were upregulated, and miR-429 was downregulated in OC tissues. Silencing of DLEU1 inhibited the proliferation, migration, and invasion of OC cells. Bioinformation and DLR assay showed that DLEU1 acted as the sponge for miR-429. Moreover, miR-429 could directly target TFAP2A and inhibit the proliferation, migration, and invasion of OC cells. Moreover, we observed a negative correlation between miR-429 and DLEU1, and between miR-429 and TFAP2A in OC tissues. The transfection of miR-429 inhibitor or pcDNA-TFAP2A reversed the inhibitory effects of si-DLEU1 on the proliferation, migration, and invasion of OC cells. Silencing of DLEU1 inhibited the proliferation, migration, and invasion of OC cells by regulating miR-429/TFAP2A axis, indicating a potential therapeutic target for OC.

Effects of 7,8-dihydroxyflavone on rat jejunal dynamics subjected to ischaemia-reperfusion injury.

It is known that 7,8-dihydroxyflavone (7,8-DHF), a synthetic agonist specific for TrkB, promotes intestinal cholinergic contraction. However, after intestinal ischaemia-reperfusion (IR) injury, how 7,8-DHF affects intestinal contractile dynamics is unknown. In this study, an IR injury model was prepared with rats subjected to 45 minutes clamping of the superior mesenteric artery. The IR injury decreased postoperative food intake and body weight, delayed defecation time, lowered intestinal propulsive rate and decreased cholinergic contraction of jejunal muscle strips, indicating the occurrence of injured jejunal contraction after IR. Feeding rats with 7,8-DHF improved these intestinal activities injured by IR, which exhibited the in vivo effect of 7,8-DHF. To explore its molecular mechanism, the expression and phosphorylation of TrkB, PLC γ1, Akt, and ERK1/2 in the jejunal strips were examined with western blots. The IR injury significantly decreased the expression and phosphorylation levels of all factors studied here. However, 7,8-DHF feeding specifically enhanced the phosphorylation of TrkB, PLC γ1 and Akt factors in both sham- and IR-operated rats, indicating that 7,8-DHF may have activated TrkB which then activated its downstream PLC γ1 and Akt. Finally, we found that 7,8-DHF augmented cholinergic receptor M3 expression somehow. These results imply a possibility that 7,8-DHF might be capable of alleviating the jejunal contractile damage caused by IR through activation of TrkB and augmentation of M3 expression.

Altered Inflammatory Pathway but Unaffected Liver Fibrosis in Mouse Models of Nonalcoholic Steatohepatitis Involving Interleukin-1 Receptor-Associated Kinase 1 Knockout.

BACKGROUND Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators in the signaling pathways of Toll-like receptors (TLRs)/IL1Rs. Targeting the IRAK4/IRAK1/TRAF6 axis and its associated pathway has therapeutic benefits in liver fibrosis. However, the function of IRAK1 itself in the development of liver fibrosis remains unknown. MATERIAL AND METHODS Irak1 global knockout (KO) mice were generated to study the functional role of Irak1 in liver fibrosis. Male Irak1 knockout and control mice were challenged with chronic carbon tetrachloride (CCl4) or fed a methionine- and choline-deficient diet (MCDD) to generate models of nonalcoholic steatohepatitis (NASH). Liver inflammation and collagen deposition were assessed by histological examination, quantitative real-time PCR (qRT-PCR), and western blotting of hepatic tissues. RESULTS The mRNA expression of the downstream inflammatory gene Il1b was significantly lower in Irak1-KO than in control mice. Irak1 ablation had little effect on inflammatory cell infiltration into livers of mice with NASH. Collagen deposition and the expression of genes related to fibrogenesis were similar in the livers of Irak1-KO and control mice exposed to CCl4 and MCDD. The loss of Irak1 did not affect lipid or glucose metabolism in these experimental models of steatohepatitis. CONCLUSIONS Irak1 knockout reduced the expression of inflammatory genes but had no effect on hepatic fibrogenesis. The Irak1-related pathway may regulate liver fibrosis via other pathways or be compensated for by other factors.

Metformin Suppresses Proliferation and Viability of Rat Pheochromocytoma Cells.

BACKGROUND Previous studies have clearly demonstrated that metformin inhibits cell proliferation and cell growth in many types of human cancers. Increased survival rates in patients with breast and lung cancer receiving metformin have also been observed. However, the effect of metformin on pheochromocytoma cells remains unexplored. MATERIAL AND METHODS Rat pheochromocytoma cells (PC12 cells) were cultured and treated with metformin or vehicle control. Cell proliferation, cell-cycle, apoptosis, genes expression, and the signaling pathways involved were analyzed in PC12 cells. RESULTS The metformin treatment reduced cell viability and proliferation in rat pheochromocytoma PC12 cells in a dose- and time-dependent manner. Furthermore, metformin exposure led to an increased apoptosis rate and cell-cycle arrest accompanied with downregulation of Ccna2 and Ccnb2. At the molecular level, the AMPK signaling pathway was activated, whereas the mTOR and ERK1/2 signaling pathways were inhibited by metformin. CONCLUSIONS Our data suggest an antiproliferative role of metformin in pheochromocytoma development, which may provide a novel option for future cancer therapy.

Modulation of integrin activation and signaling by α1/α1'-helix unbending at the junction.

How conformational signals initiated from one end of the integrin are transmitted to the other end remains elusive. At the ligand-binding ßI domain, the α1/α1'-helix changes from a bent to a straightened α-helical conformation upon integrin headpiece opening. We demonstrated that a conserved glycine at the α1/α1' junction is crucial for maintaining the bent conformation of the α1/α1'-helix in the resting state. Mutations that facilitate α1/α1'-helix unbending rendered integrin constitutively active; however, mutations that block the α1/α1'-helix unbending abolished soluble ligand binding upon either outside or inside stimuli. Such mutations also blocked ligand-induced integrin extension from outside the cell, but had no effect on talin-induced integrin extension from inside the cell. In addition, integrin-mediated cell spreading, F-actin stress fiber and focal adhesion formation, and focal adhesion kinase activation were also defective in these mutant integrins, although the cells still adhered to immobilized ligands at a reduced level. Our data establish the structural role of the α1/α1' junction that allows relaxation of the α1/α1'-helix in the resting state and transmission of bidirectional conformational signals by helix unbending upon integrin activation.

S100A6 as a potential serum prognostic biomarker and therapeutic target in gastric cancer.

BACKGROUND: Increased expression of S100A6 in many cancer tissues and its association with tumor behavior and patient prognosis were demonstrated, and there are no studies analyzing the serum levels of S100A6 in patients with gastric cancer (GC). AIM: Serum S100A6 levels were investigated as a marker of tumor aggressiveness in patients with GC, and the S100A6 gene was examined as a potential therapeutic target in GC. METHODS: Serum S100A6 levels were detected in 103 GC patients and 72 healthy subjects by ELISA. Clinicopathological features of GC patients were analyzed in correlation to serum S100A6 levels. Two small interfering RNAs against S100A6 (siRNA1-S100A6 and siRNA2-S100A6) were generated and transfected into SGC7901 cells using pSUPER gfp-neo vector, and the effects of S100A6 knockdown on cell proliferation, invasion and apoptosis were evaluated in vitro. The effects of S100A6 silencing on tumor growth and metastasis were evaluated in vivo in a pseudo-metastatic GC nude mouse model. RESULTS: Serum S100A6 levels were significantly higher in GC patients than in healthy controls (P < 0.001). Serum S100A6 levels were significantly correlated with lymph node metastasis, TNM stage, perineural invasion and vascular invasion. Serum S100A6 level was an independent predictor of overall survival. SiRNA-mediated silencing of S100A6 significantly induced apoptosis and decreased proliferation, clone formation and the invasiveness of GC SGC7901 cells in vitro and significantly reduced tumor volume and number in vivo (P < 0.01). CONCLUSION: Serum S100A6 level may serve as a potential prognostic biomarker in GC. Inhibition of S100A6 decreased the metastatic potential of GC cells.

Prognostic significance of XB130 expression in surgically resected pancreatic ductal adenocarcinoma.

BACKGROUND: XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis. However, its expression and role in pancreatic ductal adenocarcinoma (PDAC) have not been investigated. The present study was designed to clarify the prognostic significance of XB130 expression in PDAC. METHODS: A total of 76 consecutive patients with surgically resected PDAC were retrospectively reviewed. XB130 expression was detected by immunohistochemical analysis on the paraffin-embedded tumour sections. Correlation between the expression of XB130 and clinicopathological parameters was analyzed. RESULTS: XB130 expression was significantly upregulated in PDAC(56.5%, 43/76) compared to normal pancreas (0%, 0/15; P < 0.05). Increased XB130 expression was correlated with lymph node metastasis (P = 0.017), distant metastasis (P = 0.0024), high tumour-node-metastasis (TNM) stage (P =0.001), and high tumour grade (P = 0.013). The survival of 43 patients with high XB130 expression was significantly worse than that of the 33 patients with low XB130 expression (P = 0.001). Univariate analysis showed that high XB130 expression (P = 0.0045), tumour size (P = 0.024), distant metastasis (P = 0.003), TNM stage (P = 0.002) and lymphatic metastasis (P = 0.016) were independent prognostic factors of postoperative survival. Multivariate analysis using the Cox proportional hazards model showed that high XB130 expression and distant metastasis (P = 0.0239) were significant independent risk factors. CONCLUSIONS: XB130 was overexpressed in the PDAC. XB130 is a promising pathological marker for the prediction of outcome in patients with PDAC.

Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation.

BACKGROUND & AIMS: The development and progression of non-alcoholic fatty liver disease are associated with aging, obesity, and type 2 diabetes. Understanding the precise regulatory networks of this process will contribute to novel therapeutic strategies. METHODS: Hepatocyte-specific Men1 knockout mice were generated using Cre/loxP technology. Lipid and glucose metabolic phenotypes and mechanisms were investigated in aging and high-fat diet fed mice. RESULTS: The expression of menin, encoded by multiple endocrine neoplasia 1 (Men1) gene, is reduced in the liver of aging mice. Hepatocyte-specific deletion of Men1 induces liver steatosis in aging mice. Menin deficiency promotes high-fat diet-induced liver steatosis in mice. Menin recruits SIRT1 to control hepatic CD36 expression and triglyceride accumulation through histone deacetylation. CONCLUSIONS: Our work reveals that the adaptor protein menin is critical for the progression of hepatic steatosis during aging and metabolic imbalance.

Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity.

Glioblastoma contains a hierarchy of stem-like cancer cells, but how this hierarchy is established is unclear. Here, we show that asymmetric Numb localization specifies glioblastoma stem-like cell (GSC) fate in a manner that does not require Notch inhibition. Numb is asymmetrically localized to CD133-hi GSCs. The predominant Numb isoform, Numb4, decreases Notch and promotes a CD133-hi, radial glial-like phenotype. However, upregulation of a novel Numb isoform, Numb4 delta 7 (Numb4d7), increases Notch and AKT activation while nevertheless maintaining CD133-hi fate specification. Numb knockdown increases Notch and promotes growth while favoring a CD133-lo, glial progenitor-like phenotype. We report the novel finding that Numb4 (but not Numb4d7) promotes SCF(Fbw7) ubiquitin ligase assembly and activation to increase Notch degradation. However, both Numb isoforms decrease epidermal growth factor receptor (EGFR) expression, thereby regulating GSC fate. Small molecule inhibition of EGFR activity phenocopies the effect of Numb on CD133 and Pax6. Clinically, homozygous NUMB deletions and low Numb mRNA expression occur primarily in a subgroup of proneural glioblastomas. Higher Numb expression is found in classical and mesenchymal glioblastomas and correlates with decreased survival. Thus, decreased Numb promotes glioblastoma growth, but the remaining Numb establishes a phenotypically diverse stem-like cell hierarchy that increases tumor aggressiveness and therapeutic resistance.

Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.

Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways.

Effect of high-fructose consumption in pregnancy on the bone growth of offspring rats.

Growing evidence suggests that bone health is programmed in early life. Maternal diet may influence the skeletal development of offspring. We aimed to determine the possible effects of high-fructose intake during pregnancy on different aspects of long bone morphology in the offspring of rats and to initially explore the possible mechanisms. Pregnant Sprague-Dawley rats were randomly divided into four groups and intragastrically administered the same dose of distilled water (CON, n = 12), 20 g/kg/day glucose (GLU, n = 12), 10 g/kg/day fructose (LFRU, n = 12), or 20 g/kg/day fructose (HFRU, n = 12) for 21 days during gestation. Computed tomography was used to analyze the cortical and cancellous bones of the distal femur of the offspring rats, and circulating bone metabolic biomarkers were measured using enzyme immunoassay. The results showed that high-fructose intake during pregnancy could decrease body weight, impair glucose metabolism, and increase serum leptin and uric acid in offspring. The offspring in the HFRU group had higher levels of the N-terminal propeptide of type I procollagen (PINP) and the C-telopeptide of type I collagen (CTX). The bone mean density (BMD), the total cross-sectional area inside the periosteal envelope (Tt.Ar), cortical bone area (Ct.Ar), medullary (or marrow) area (Ma.Ar), and trabecular mean density of the offspring in the HFRU group were lower than those in the CON group. Tartrate-resistant acid phosphatase (Trap) staining showed that high-fructose intake during pregnancy could increase the number of osteoclasts and increase the absorption area. Our results suggested that excessive fructose intake during pregnancy could inhibit skeletal development in offspring. Thus, attention to fructose intake during pregnancy is important for bone development in offspring.

MicroEXPERT: Microbiome profiling platform with cross-study metagenome-wide association analysis functionality.

The framework of the MicroEXPERT platform. Our Platform was composed of five modules. Data management module: Users upload raw data and metadata to the system using a guided workflow. Data processing module: Uploaded data is processed to generate taxonomical distribution and functional composition results. Metagenome-wide association studies module (MWAS): Various methods, including biomarker analysis, PCA, co-occurrence networks, and sample classification, are employed using metadata. Data search module: Users can query nucleotide sequences to retrieve information in the MicroEXPERT database. Data visualization module: Visualization tools are used to illustrate the metagenome analysis results.

Analysis of Factors Influencing Depression in Elderly People Living with HIV/AIDS Based on Structural Equation Model: A Cross-Sectional Study in Guangxi, China.

Purpose: The purpose of our study is to understand the current status of depression and medical social support in elderly HIV/AIDS, as well as the role of social support on depression, so as to provide a certain reference for reducing the occurrence of depression in the population. Methods: A total of 115 participants with PLWHA (people living with HIV/AIDS) aged 50 years or older were collected in Guilin from December 2021 to July 2022. Depression and medical social support were assessed using the Center for Streaming Depression Scale (CES-D) and the Medical Social Support Scale (MOS-SSS). The structural equation model was used to examine the relationship between medical social support and depression. Results: Sixty-one of 115 participants developed depressive symptoms with a prevalence of 53.0%. The results of univariate analysis showed that ethnicity, health status, mean monthly income, antiviral treatment status, and medical social support influenced PLWHA depression (P<0.05). Simple linear regression showed that health status (95% CI: -9.901~-2.635), and antiviral treatment status (95% CI: -12.969~-3.394) influent depression (P<0.05). There were associations between total medical social support, practical support dimension, message and emotional support dimension, social interactive cooperation dimension, emotional support dimension and depression (unadjusted and adjusted for contextual factors) (P < 0.05). Using multiple linear regression analyses, we found that medical-social support was negatively associated with depression with a standardized effect value of -0.223. PLWHA with higher medical social support had lower prevalence of depression. Conclusion: The results indicate that the prevalence of depression among HIV/AIDS patients in Guilin is high. So the joint efforts of individuals, families, and society are needed to improve the physical and mental health of the PLWHA.

Let7b-5p inhibits insulin secretion and decreases pancreatic ß-cell mass in mice.

MicroRNAs are crucial regulators for the development, mass and function of pancreatic ß-cells. MiRNA dysregulation is associated with ß-cell dysfunction and development of diabetes. The members of let7 family are important players in regulating cellular growth and metabolism. In this study we investigated the functional role of let7b-5p in the mouse pancreatic ß-cells. We generated pancreatic ß-cell-specific let7b-5p transgenic mouse model and analyzed the glucose metabolic phenotype, ß-cells mass and insulin secretion in vivo. Luciferase reporter assay, immunofluorescence staining and western blot were carried out to study the target genes of let7b-5p in ß-cells. Let7b-5p overexpression impaired the insulin production and secretion of ß-cells and resulted impaired glucose tolerance in mice. The overexpressed let7b-5p inhibited pancreatic ß-cell proliferation and decreased the expression of cyclin D1 and cyclin D2. Our findings demonstrated that let7b-5p was critical in regulating the proliferation and insulin secretion of pancreatic ß-cells.

The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.

The imprinted gene PEG3 confers parenting and sexual behaviors, alters growth and development, and regulates apoptosis. However, a molecular mechanism that can account for the diverse functions of Peg3/Pw1 is not known. To elucidate Peg3-regulated pathways, we performed a functional screen in zebrafish. Enforced overexpression of PEG3 mRNA during zebrafish embryogenesis decreased beta-catenin protein expression and inhibited Wnt-dependent tail development. Peg3/Pw1 also inhibited Wnt signaling in human cells by binding to beta-catenin and promoting its degradation via a p53/Siah1-dependent, GSK3beta-independent proteasomal pathway. The inhibition of the Wnt pathway by Peg3/Pw1 suggested a role in tumor suppression. Hypermethylation of the PEG3 promoter in primary human gliomas led to a loss of imprinting and decreased PEG3 mRNA expression that correlated with tumor grade. The decrease in Peg3/Pw1 protein expression increased beta-catenin, promoted proliferation, and inhibited p53-dependent apoptosis in human CD133(+) glioma stem cells. Thus, mammalian imprinting utilizes Peg3/Pw1 to co-opt the Wnt pathway, thereby regulating development and glioma growth.

Components characterisation of Berchemia lineata (L.) DC. by UPLC-QTOF-MS/MS and its metabolism with human liver microsomes.

Investigations were performed on the determination of the main components in Berchemia lineata (L.) DC. (BL) and its metabolism with human liver microsomes (HLM). A total of 35 compounds were detected in BL extracts and 25 of them including 6 naphthopyrones, 10 flavonoids, 2 phenolic acids, 2 phenols, 4 fatty acids and 1 quinone were unambiguously or tentatively identified by UPLC-QTOF-MS/MS. Among them, naphthopyrones were first identified in BL extracts and labelled in chromatography. In addition, the weak inhibitory effects of BL extracts (IC50＝149.25 µg/mL) and rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glu-copyranside (the main component of BL extracts, M0; IC50＝82.14 µM) on CYP3A4 were also proved using testosterone as specific probe drug. The main metabolic pathway of M0 by HLM was hydroxylation in its aglycone, the metabolite was tentatively identified as 10-hydroxy-rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glucopyranside. Components characterisation and the metabolism with HLM could help the further development and application of BL.

YY1 deficiency in ß-cells leads to mitochondrial dysfunction and diabetes in mice.

BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic ß-cells, however, the physiological functions of YY1 in ß-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of ß-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, ß-cell mass and ß-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of ß-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in ß-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, ß-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic ß-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in ß-cells.

MiR-221/222 Inhibit Insulin Production of Pancreatic ß-Cells in Mice.

Microribonucleic acids (miRNAs) are essential for the regulation of development, proliferation, and functions of pancreatic ß-cells. The conserved miR-221/222 cluster is an important regulator in multiple cellular processes. Here we investigated the functional role of miR-221/222 in the regulation of ß-cell proliferation and functions in transgenic mouse models. We generated 2 pancreatic ß-cell-specific-miR-221/222 transgenic mouse models on a C57BL/6J background. The glucose metabolic phenotypes, ß-cell mass, and ß-cell functions were analyzed in the mouse models. Adenovirus-mediated overexpression of miR-221/222 was performed on ß-cells and mouse insulinoma 6 (MIN6) cells to explore the effect and mechanisms of miR-221/222 on ß-cell proliferation and functions. Luciferase reporter assay, histological analysis, and quantitative polymerase chain reaction (PCR) were carried out to study the direct target genes of miR-221/222 in ß-cells. The expression of miR-221/222 was significantly upregulated in ß-cells from the high-fat diet (HFD)-fed mice and db/db mice. Overexpression of miR-221/222 impaired the insulin production and secretion of ß-cells and resulted in glucose intolerance in vivo. The ß-cell mass and proliferation were increased by miR-221/222 expression via Cdkn1b and Cdkn1c. MiR-221/222 repressed insulin transcription activity through targeting Nfatc3 and lead to reduction of insulin in ß-cells. Our findings demonstrate that miR-221/222 are important regulators of ß-cell proliferation and insulin production. The expression of miR-221/222 in ß-cells could regulate glucose metabolism in physiological and pathological processes.

Aberrant splicing of cyclin-dependent kinase-associated protein phosphatase KAP increases proliferation and migration in glioblastoma.

The cyclin-dependent kinase (Cdk)-associated protein phosphatase KAP is a dual-specificity phosphatase of which the only known function is to dephosphorylate Cdk2 and inhibit cell cycle progression. Paradoxically, we find increased KAP mRNA expression in malignant astrocytomas, which correlates with increasing histologic grade and decreased patient survival. We have resolved this apparent paradox with the discovery of aberrant KAP splicing in malignant astrocytomas that leads to increased expression of KAP-related transcripts but decreased KAP protein expression. In addition, the aberrant splicing generates a dominant negative KAP variant that increases proliferation. We provide the first evidence that KAP not only regulates proliferation but also inhibits migration by decreasing cdc2 mRNA and protein expression. The effect of KAP on cdc2 expression requires its phosphatase activity but does not involve direct dephosphorylation of cdc2. Thus, KAP regulates both cdc2-dependent migration and Cdk2-dependent proliferation, and its loss due to aberrant splicing increases malignancy in human gliomas.

MicroRNA-935 acts as a prognostic marker and promotes cell proliferation, migration, and invasion in colorectal cancer.

Colorectal cancer (CRC) is a common cause of cancer-related deaths worldwide. MicroRNA-935 (miR-935) has been reported to be involved in several cancers. In the present study, we aimed to investigate the role of miR-935 in the progression of CRC. The expression levels of miR-935 in CRC tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The prognostic significance of miR-935 was identified using Kaplan-Meier survival analysis and Cox regression assay. Cell proliferation capacity was detected by Cell Counting Kit-8 (CCK-8) assay. Cell migration and invasion capacities were determined by Transwell assay in CRC cells. Bioinformatics analysis and luciferase reporter assays were used to confirm the direct target of miR-935. The expression of miR-935 was increased in CRC tissues and cells. Overexpression of miR-935 was significantly associated with lymph node metastasis and TNM stage. Overexpression of miR-935 in patients predicted shorter overall survival compared to low miR-935 expression. The expression of miR-935 was indicated to be an independent prognostic factor for CRC patients. In addition, overexpression of miR-935 in CRC cells promoted cell proliferation, migration, and invasion, whereas inhibition of miR-935 suppressed cell proliferation, migration, and invasion. Bioinformatics and luciferase assays revealed that INPP4A is a direct target of miR-935. Our findings suggest that miR-935 functions as an oncogene and promotes CRC progression. INPP4A is a potential target of miR-935. And miR-935 may represent a prognostic biomarker and potential therapeutic strategy for CRC treatment.