📋 Browse Articles

The cytoplasmic protein AXIN1 is involved in the Wnt signalling pathway and its expression is increased in patients with endometriosis compared with healthy controls. The aim of the present cross-sectional study was to further assess the levels of AXIN1 and other inflammatory biomarkers in patients with endometriosis. Patients with laparoscopy-verified endometriosis were recruited (n=172) and completed a questionnaire regarding socioeconomic factors, lifestyle habits and medical history. Plasma AXIN1 and high-sensitivity C-reactive protein (hs-CRP) levels were analysed by ELISA. The levels of calprotectin were determined in the faeces, and the haemoglobin concentration and number of erythrocytes, leukocytes and platelets were determined in the blood in a subgroup of 64 patients during clinical routine procedures. F-calprotectin expression was detected in 18 women (28.1%), who had more severe constipation and more frequently experienced incomplete evacuation when defecating, and 5 women (7.8%) exhibited elevated levels. P-AXIN1 levels were higher in patients who received hormonal treatment, and correlated inversely with faecal-calprotectin levels (P=0.003), B-haemoglobin levels (P=0.030) and the numbers of B-erythrocytes (P=0.033) and B-platelets (P=0.017), but were not correlated with hs-CRP levels (P=0.818). Higher levels of AXIN1 were associated with the duration of the gastrointestinal symptoms and with diarrhoea, constipation, vomiting and nausea and the intestinal symptoms' effect on quality of life, and tended to be associated with the duration of endometriosis. Hs-CRP expression was not associated with the clinical characteristics or symptoms of endometriosis, but higher levels were associated with obesity (P=0.002) and hormonal treatment (P=0.011). In conclusion, P-AXIN1 expression was negatively correlated with certain inflammatory biomarkers and was positively associated with gastrointestinal symptoms. P-AXIN1 levels were increased in patients who received hormonal treatment, highlighting the importance of obtaining native samples for future studies regarding its role in the development and presentation of endometriosis. However, hs-CRP and other studied biomarkers seemed to be of no value for the assessment and diagnosis of endometriosis. Show less

Emerging evidence shows that frequent recurrence of intracranial aneurysms (IAs) after endovascular coiling is attributable to the lack of endothelialization across the aneurysm neck. Recently, much attention has been given to the role of microRNAs (miRs) in vascular disease, although their contributory role to IA is poorly understood. Adult male Sprague-Dawley rats were subjected to microsurgery to create a coiled embolization aneurysm model, and were injected with miR-31a-5p agomir or a negative control agomir via the tail vein at a dose of 10 mg/kg per week for 4 weeks after IA induction. H & E staining, scanning electron microscopy, and flow cytometry were performed to evaluate the effects of miR-31a-5p agomir on endothelialization and the number of circulating endothelial progenitor cells (EPCs). The effects of miR-31a-5p on the viability and functioning of EPCs were also determined using Cell Counting Kit-8, wound-healing assay, and tube formation assays. The authors tested the ability of miR-31a-5p to promote EPC-induced endothelialization in a model of coiled embolization aneurysm. miR-31a-5p agomir improved endothelialization and elevated the number of circulating EPCs in the peripheral blood compared to a negative control agomir-treated group. In addition, the number of vWF- and KDR-positive cells in the aneurysm neck was increased in the miR-31a-5p agomir-treated group. Furthermore, upregulation of miR-31a-5p promoted EPC proliferation, migration, and tube formation and enhanced the expression of the proangiogenic factor vascular endothelial growth factor in vitro. Mechanistically, miR-31a-5p directly targeted the 3' untranslated region (3'UTR) of Axin1 messenger RNA and repressed its expression. Besides, miR-31a-5p exerted its effect on EPCs by regulating the Axin1-mediated Wnt/β-catenin pathway. Collectively, these results indicate that miR-31a-5p is an important regulator of EPC mobilization and endothelialization and may have a positive effect on aneurysm repair. Show less

Colorectal cancer (CRC) is the leading cause of cancer death, and its 5-year survival rate remains unsatisfactory. Recent studies have revealed that ubiquitin-specific protease 44 (USP44) is a cancer suppressor or oncogene depending on the type of neoplasm. However, its role in CRC remains unclear. Here, we found that the USP44 expression level was markedly decreased in CRC, and USP44 overexpression inhibited proliferation while enhancing apoptosis in CRC cells, suggesting that USP44 is a cancer suppressor in CRC. We then investigated if USP44 functioned through regulating the Wnt/β-catenin pathway. We found that USP44 overexpression increased the Axin1 protein while decreasing β-catenin, c-myc, and cyclin D1 proteins, suggesting that USP44 inhibited the activation of the Wnt/β-catenin pathway. Moreover, we found that two Wnt/β-catenin activators, LiCl and SKL2001, both attenuated oeUSP44-mediated proliferation and apoptosis in CRC cells. Collectively, these data points indicated that USP44 inhibited proliferation while promoting apoptosis in CRC cells by inhibiting the Wnt/β-catenin pathway. Interestingly, we observed that USP44 overexpression did not affect the Axin1 mRNA level. Further study uncovered that USP44 interacted with Axin1 and reduced the ubiquitination of Axin1. Furthermore, Axin1 knock-down abolished the effects of oeUSP44 on proliferation, apoptosis, and Wnt/β-catenin activity in CRC cells. Taken together, this study demonstrates that USP44 inhibits proliferation while enhancing apoptosis in CRC cells by inactivating the Wnt/β-catenin pathway via Axin1 deubiquitination. USP44 is a cancer suppressor in CRC and a potential target for CRC therapy. Show less

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate and low survival rate. This study was designed to explore a novel molecular with high sensitivity and specificity, which can be applied in early diagnosis and therapeutic evaluation of HCC. The current study aims to investigate the effect and important role of Axin1 on cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma. qRT-PCR results showed lower Axin1 expression level and higher miR-650 expression level in HCC. Luciferase reporter assay was carried out to verify the negative correlation between Axin1 and miR-650 mRNA levels. CCK-8 assay results showed that the cell proliferation ability was significantly suppressed by Axin1 overexpression in SK-HEP-1 cells. The results in wound healing assay uncovered that cell migration ability was markedly suppressed by Axin1 overexpression. The results in trans-well invasion assay showed that Axin1 overexpression caused decreased invasive ability in SK-HEP-1 cells. The WB results showed that the protein level of E-cad was significantly increased and the protein levels of N-cad, vimentin and snail were obviously reduced following Axin1 overexpression. Whereas, the suppressive effects on cell proliferation, migration, invasion and EMT caused by Axin1 overexpression were abolished by miR-650 mimic. All the results in the current study confirmed the truth that Axin1 overexpression could suppress cell proliferation, migration, invasion and EMT by downregulating miR-650 expression. Show less

Ovarian carcinoma ranks fifth in the leading causes of cancer-relevant deaths among the female, with the highest fatality rate in all gynecological malignant tumors and the rising incidence worldwide. Mounting evidence has unveiled that lncRNAs are implicated in the tumorigenesis and cancer development. Several studies have proven the carcinogenic role of SNHG8 in various malignancies, but the physiological functions of SNHG8 in ovarian carcinoma need more detailed explanations. The present study certified that inhibition of SNHG8 executed suppressive activities in ovarian carcinoma by obstructing cell proliferation, migration, EMT process and stemness as well as driving cell apoptosis. Moreover, SNHG8 bound with CAPRIN1 and positively modulated the expression of CAPRIN1. Further experiments manifested that CTNNB1 and Axin1 displayed a binding affinity with CAPRIN1. Knockdown of CAPRIN1 promoted the mRNA degradation of CTNNB1 and Axin1. Finally, we corroborated that CTNNB1 (or Axin1) ectopic expression or activation of Wnt/β-catenin pathway abrogated the effects of SNHG8 downregulation on the cellular process of ovarian carcinoma cells. To summarize, SNHG8 acted as an oncogene in ovarian carcinoma via targeting Wnt/β-catenin pathway, providing a new insight into understanding ovarian carcinoma at the molecular level. Show less

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and relapse rates. Even though changes in inflammatory markers and cytokines are known to accompany cachexia associated with somatic disorders such as cancer and chronic kidney disorder, studies on inflammatory markers in AN are rare and typically include few individuals. Here, we utilize an Olink Proteomics inflammatory panel to explore the concentrations of 92 preselected inflammation-related proteins in plasma samples from women with active AN (N = 113), recovered from AN (AN-REC, N = 113), and normal weight healthy controls (N = 114). After correction for multiple testing, twenty-five proteins differed significantly between the AN group and controls (lower levels: ADA, CCL19, CD40, CD5, CD8A, CSF1, CXCL1, CXCL5, HGF, IL10RB, IL12B, 1L18R1, LAP TGFß1, MCP3, OSM, TGFα, TNFRSF9, TNFS14 and TRANCE; higher levels: CCL11, CCL25, CST5, DNER, LIFR and OPG). Although more than half of these differences (N = 15) were present in the comparison between AN and AN-REC, no significant differences were seen between AN-REC and controls. Furthermore, twenty-five proteins correlated positively with BMI (ADA, AXIN1, CASP8, CD5, CD40, CSF1, CXCL1, CXCL5, EN-RAGE, HGF, IL6, IL10RB, IL12B, IL18, IL18R1, LAP TGFß1, OSM, SIRT2, STAMBP, TGFα, TNFRSF9, TNFS14, TRANCE, TRAIL and VEGFA) and four proteins correlated negatively with BMI (CCL11, CCL25, CCL28 and DNER). These results suggest that a dysregulated inflammatory status is associated with AN, but, importantly, seem to be confined to the acute illness state. Show less

The Wingless-type (Wnt) signaling pathway plays an important role in the development and progression of cancer. This study aimed to evaluate the relationship between single nucleotide polymorphisms (SNPs) in the Wnt pathway and the risk of bone metastasis in patients with non-small cell lung cancer (NSCLC). We collected 500 blood samples from patients with NSCLC and genotyped eight SNPs from four core genes (WNT2, AXIN1, CTNNB1 and APC) present within the WNT pathway. Moreover, we assessed the potential relationship of these genes with bone metastasis development. Our results showed that the AC/AA genotype of CTNNB1: rs1880481 was associated with a decreased risk of bone metastasis. Polymorphisms with an HR of < 1 had a cumulative protective impact on the risk of bone metastasis. Furthermore, patients with the AC/AA genotype of CTNNB1: rs1880481 was associated with Karnofsky performance status score, squamous cell carcinoma antigen and Ki-67 proliferation index. Lastly, patients with the AC/AA genotype of CTNNB1: rs1880481 had significantly longer median progression free survival time than those with the CC genotype. In conclusion, SNPs within the Wnt signaling pathway are associated with a decreased risk of bone metastasis, and may be valuable biomarkers for bone metastasis in patients with NSCLC. Show less

Micropapillary-predominant adenocarcinoma (MPA) of the lung is associated with extensive lymph node involvement and rapid terminal metastasis. However, this subtype has been recognized for only a few years, and there have been few studies of the molecular mechanisms associated with its highly invasive behaviors. The present study utilized immunohistochemical staining of surgically resected tissue blocks of MPA and lepidic-predominant lung adenocarcinoma to quantify the expression of specific biological markers in the WNT/β-catenin pathway and evaluate their influence on the lymph nodes invasion of these two types of lung adenocarcinomas. Our findings revealed that disruption of the cell membrane cadherin-catenin complex, which weakens the tumor cell adherence of MPA, was caused by the dissociation of β-catenin from the cadherin-catenin complex and the subsequent accumulation of β-catenin in the cytoplasm. This caused abnormal activation of the WNT/β-catenin pathway. We also found that Wnt-1-specific overexpression and Axin1 inhibition in MPA could explain the redistribution and cytoplasmic retention of β-catenin. Collectively, these findings suggest that an abnormality in the WNT/β-catenin pathway could enhance the invasiveness of MPA through the overexpression of Wnt-1 and downregulation of Axin1 molecules. Our data support the need for further research regarding the WNT/β-catenin pathway and the need to develop novel targeted therapies for restoration of tumor cell adherence and improvement of the prognosis of MPA. Show less

Ethyl 2-acrylamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate as well as its corresponding bis-derivatives, 5-10, with aliphatic linkers were synthesized, fully characterized, and tested as novel anticancer agents. The targeted compounds, 5-10, were obtained by the Knoevenagel condensation reactions of bis-o- or -p-aldehyde with a molar ratio of ethyl 2-(2-cyanoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate of 2 in the presence of piperidine in excellent yields (93-98%). The in vitro anticancer activities of the prepared compounds were evaluated against HepG2, MCF-7, HCT-116, and BJ1 cells. Compounds 7 and 9 emerged as the most promising compounds, with IC Show less

Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. Show less

Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both Show less

Objective To construct the axis inhibition protein 1 (AXIN1) gene-knockout ACT-1 human undifferentiated thyroid cancer single clone cell line. Methods Molecular cloning technology and clustered regularly interspaced short palindromic repeats/Cas9 nuclease (CRISPR/Cas9) were used to construct AXIN1 gene-knockout single clone cell lines. Real-time quantitative PCR and Western blotting were used to detect AXIN1 mRNA and protein levels of ACT-1 cells, respectively. Results T7 detection results showed two effective single guide RNAs (sgRNAs) Cr3 and Cr5 were successfully constructed; enzyme digestion identification and sequencing showed AXIN1-targeted sgRNA viral vectors carrying green fluorescent protein (GFP) were successfully constructed. We successfully obtained 4 monoclonal ACT-1 undifferentiated thyroid cancer cell lines. AXIN1 mRNA and protein levels in the gene-knockout group were significantly reduced. Conclusion The ACT-1 undifferentiated thyroid cancer cell line with AXIN1 gene knockout has been successfully constructed using CRISPR/Cas9. Show less

Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, β-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity. Show less

Dysregulation of the Wnt/β-catenin signaling pathway is involved in the development of human hepatocellular carcinoma and has thus emerged as a therapeutic target for this malignant tumor. In this study, we employed sensitive cell-based assays to identify aplykurodin A isolated from Show less

In this study, the role of ubiquitin conjugating enzyme E2 M (UBE2M) and molecular mechanisms associated with osteoarthritis (OA) were explored. Cartilage tissues and corresponding healthy tissues from OA patients were isolated. Our data suggested that the expression level of UBE2M in OA patients was significantly higher compared to that in healthy individuals (P < 0.01). The apoptosis of human OA chondrocytes was inhibited when silencing UBE2M and increased when overexpressing UBE2M. XAV939, as a tankyrase 1 inhibitor, could block the signaling pathway of Wnt/β-catenin, which significantly reversed the change introduced by UBE2M. The expression level of cytoplasmic β-catenin in siUBE2M cells dramatically increased, and the expression levels of nuclear β-catenin, cleaved caspase-3 (C-caspase-3), and MMP13 remarkably downregulated. Moreover, the ubiquitination of Axin was enhanced by the overexpression of UBE2M. The expression level of Axin significantly decreased in OA chondrocytes with UBE2M overexpression and increased after MG132 treatment. Moreover, UBE2M enhanced the apoptosis of OA chondrocytes by activating the Axin-dependent Wnt/β-catenin pathway. In this process, UBE2M downregulated Axin in an ubiquitination-dependent degradation pathway and subsequently activated Wnt/β-catenin signaling. Show less

Aberrant activation of the WNT/CTNNB1 pathway is notorious in colorectal cancer (CRC). Here, we demonstrate that the expression of specific and crucial WNT signaling pathway genes is linked to disease progression in colonic adenomatous (AP) and hyperplastic (HP) polyps in an Iranian patient population. Thus, we highlight potential gene expression profiles as candidate novel biomarkers for the early detection of CRC. From a 12-month study (2016-2017), 44 biopsy samples were collected during colonoscopy from the patients with colorectal polyps and 10 healthy subjects for normalization. Clinical and demographic data were collected in all cases, and mRNA expression of APC, CTNNB1, CDH1, AXIN1, and AXIN2 genes was investigated using real-time polymerase chain reaction (PCR). CTNNB1 and CDH1 expression levels were unaltered in AP and HP subjects, whereas mRNA expression of APC was decreased in AP contrasted with HP subjects, with a significant association between APC downregulation and polyp size. Although AXIN1 showed no changes between AP and HP groups, a significant association between AXIN1 and dysplasia grade was found. Also, significant upregulation of AXIN2 in both AP and HP subjects was detected. In summary, we have shown increased expression of AXIN2 and decreased expression of APC correlating with grade of dysplasia and polyp size. Hence, AXIN2 and APC should be explored as biomarker candidates for early detection of AP and HP polyps in CRC. Show less

Proteomic-based technologies offer new opportunities to identify proteins that might reflect the cardiometabolic stress caused by different aspects of sleep-disordered breathing. We aimed to investigate whether severe obstructive sleep apnea and severe obstructive sleep apnea during rapid eye movement sleep are associated with changed levels of inflammatory and cardiac disease-related proteins in a population-based cohort of women. In the community-based "Sleep and Health in Women" (SHE) cohort study, 400 women underwent polysomnography, anthropometric measurements and blood sampling. Two proteomic assays (Olink Proseek Show less

Non-small-cell lung cancer (NSCLC) remains a highly prevalent and deadly form of cancer, with efforts to better understand the molecular basis of the progression of this disease being essential to its effective treatment. Several recent studies have highlighted the ability of RNA-binding proteins (RBPs) to regulate a wide range of cellular processes in both healthy and pathogenic contexts. Among these RBPs, RNA binding motif protein 47 (RBM47) has recently been identified as a tumor suppressor in both breast and colon cancers, whereas its role in NSCLC is poorly understood. RBM47 expression in NSCLC samples was evaluated by RT-PCR, western blotting and immunohistochemistry analysis. Molecular and cellular techniques including lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of RBM47. This study sought to analyze the expression and role of RBM47 in NSCLC. In the present study, we observed reduced levels of RBM47 expression in NSCLC, with these reductions corresponding to a poorer prognosis and more advanced disease including a higher TNM stage (p = 0.022), a higher likelihood of tumor thrombus (p = 0.001), and pleural invasion (p = 0.033). Through functional analyses in vitro and in vivo, we further demonstrated that these RBP was able to disrupt the proliferation, migration, and invasion of NSCLC cells. At a molecular level, we determined that RBM47 was able to bind the AXIN1 mRNA, stabilizing it and thereby enhancing the consequent suppression of Wnt/β-catentin signaling. Together our findings reveal that RBM47 targets AXIN1 in order to disrupt Wnt/β-catenin signaling in NSCLC and thereby disrupting tumor progression. These results thus offer new insights into the molecular biology of NSCLC, and suggest that RBM47 may also have value as a prognostic biomarker and/or therapeutic target in NSCLC patients. Show less

Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway. Show less

Treatment of HIV-1-infected patients results in improved clinical and immunological conditions, but severe non-AIDS-related conditions still persist. Novel proteomic platforms have identified inflammatory proteins where abundance is dysregulated in adult treated patients, whereas limited data are available in treated HIV-1 infection of children. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we analyzed specimens from 43 vertically HIV-1-infected children receiving antiretroviral treatment (ART) and matched controls in Ethiopia. The infected children were analyzed as a group and separately, according to age of treatment initiation. Proteins displaying a significantly different abundance between groups were hierarchically clustered and presented in heat maps. Random forest analysis was performed to pin-point proteins discriminating between groups; five proteins (STAMBP, CD5, TFG-α, TRANCE, AXIN1) were the strongest prediction factors for treated HIV-1 infection. TRANCE was previously linked to reduced bone mass levels in HIV-1-infected children. CCL4 chemokine, ligand to HIV-1 co-receptor CCR5, was the most critical protein for successful classification between children who initiated ART at different time points. Our data provide evidence that a dysregulated expression of proteins linked to immunological abnormalities and bone metabolism can be found in HIV-1-infected children with prolonged exposure to ART. Show less

Spermatogonial stem cells and organ engineering research has raised new hope in infertility treatment. Spermatogenesis is a complex physiological process. To observe the proliferation ability and differentiation tendency of mice spermatogonial stem cells (SSCs), to study the effect of regulating the Wnt signaling pathway on the proliferation and differentiation of SSCs, and to provide a valuable basis for the clinical application of SSCs. SSCs were isolated and cultured by immunomagnetic separation. Cell surface markers were identified by flow cytometry. Axin1 was chosen as the target gene to inhibit fibrosis of SSCs by inhibiting the activity of Wnt signaling pathway. Axin-siRNA interference vector was constructed and transfected into spermatogonial stem cells. Cultured SSCs were randomly divided into six groups: control group, SSCs + TGF-β group, SSCs + DKK1 group, SSCs + Axin-RNAi group, SSCs + TGF-β + DKK1 group, SSCs + TGF-β + Axin-RNAi group. Proliferation of SSCs in each group was detected by MTT assay. Immunofluorescence, western blot and real time polymerase chain reaction analysis were used to detect protein expression in the Wnt/β catenin signaling pathways and the molecular markers of fibroblasts in SSCs. Flow cytometry analysis confirmed that the cultured SSCs were of high purity. MTT assay showed there was no significant difference between Axin-siRNA transfected and non-transfected cells. The proliferation ability was significantly increased in the SSCs + TGF-β group, however, it was retarded in SSCs + Axin-RNAi group. The results of immunofluorescence and western blot analysis showed that the expression levels of the Wnt signaling pathway proteins were relatively inhibited after Axin-siRNA was applied. Real-time polymerase chain reaction showed that the expression levels of the molecular markers of fibroblasts were close to the normal control group. The Axin-siRNA constructed in this study specifically inhibited Wnt/β-catenin signal pathway activation, then inhibited the differentiation of SSCs into fibroblasts, which provides a valuable basis for the clinical application of SSCs. Show less

The authors' previous study demonstrated that miR‑128 may exert an inhibitory effect on the osteogenic differentiation of bone marrow‑derived mesenchymal stem cells (BM‑MSCs), but its downstream mechanisms remain to be elucidated. The aim of the present study was to investigate the microRNA (miRNA/miR) and mRNA profiles of differentiated and undifferentiated BM‑MSCs and explore new downstream targets for miR‑128. The sequencing datasets of GSE107279 (miRNA) and GSE112318 (mRNA) were downloaded from the Gene Expression Omnibus database. The differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using the DESeq2 method. The target genes of DEMs were predicted by the miRwalk 2.0 database. The hub target genes of miR‑128 were screened by constructing the protein‑protein interaction (PPI) network and module analysis. The expression levels of miR‑128 and crucial target genes were validated by reverse transcription‑quantitative (RT‑q) PCR before or after transfection of miR‑128 mimics to BM‑MSCs. The miRNA expression profile analysis identified miR‑128 as one of the significantly downregulated DEMs (total 338) in differentiated BM‑MSCs compared with the undifferentiated control. A total of 103 predicted target genes of miR‑128‑3p were overlapped with upregulated DEGs. By calculating the topological properties of each protein in the PPI network, 6 upregulated genes (KIT, NTRK2, YWHAB, GAB1, AXIN1 and RUNX1; fold change was the highest for NTRK2) were considered to be hub genes. Of these, 4 were enriched in module 4 (RUNX1, KIT, GAB1 and AXIN1; RUNX1 was particularly crucial as it can interact with the others), while one was enriched in module 7 (YWHAB). The expression levels of miR‑128 and these 6 target genes during the osteogenic differentiation were experimentally confirmed by RT‑qPCR. In addition, the expression levels of these 6 genes were significantly reversed after transfection of miR‑128‑3p mimics into rat BM‑MSCs compared with the miR‑control group. These findings indicated that miR‑128‑3p may inhibit the osteoblast differentiation of BM‑MSCs by downregulation of these 6 genes, particularly RUNX1, YWHAB and NTRK2. Show less

Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC is an essential component of a cytoplasmic protein complex that targets β-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous β-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/β-catenin signaling such that in response to Wnt, the β-catenin destruction complex: (1) maintains composition and binding to β-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization. Show less

Lymphoma, a malignant tumor, is mainly characterized by painless lymph node enlargement and hepatosplenomegaly. At present, lymphoma is mainly treated by radiation, chemical drugs, bone marrow transplantation and surgery. However, due to the high degree of heterogeneity, lymphomas are highly different in terms of treatment intensity and prognosis. This study is designed to investigate the function of tripartite motif-containing 11 (TRIM11) in lymphomas. The expression of TRIM11 in lymphoma tissues and multiple lymphoma cell lines was respectively detected by microarray immunohistochemistry, real-time PCR and Western blotting. After TRIM11 knockdown, overexpression, or β-catenin inhibitor XAV939 treatment, proliferation, apoptosis and cell cycle progression, as well as expression of related-genes were detected. Next, Co-Immunoprecipitation (Co-IP) and ubiquitination detection were performed. Elevated expression of tripartite motif-containing 11 (TRIM11) was observed in lymphoma tissues and multiple lymphoma cell lines (Raji, Jurkat, U937 and Hut78). Knockdown of TRIM11 in lymphoma cells significantly suppressed cell proliferation and prevented cell cycle progression from entering S or G2 phase. Concurrently, the expression of β-catenin, Cyclin D1 and c-Myc proteins in TRIM11-silenced lymphoma cells was decreased, while Axin1 was increased. In addition, TRIM11 overexpression had an opposite effect to TRIM11 knockdown, and a β-catenin inhibitor, XAV939, potently attenuated the induction of TRIM11 on lymphoma cells. Co-IP assay showed the interaction of TRIM11 and Axin1, and TRIM11 knockdown inhibited Axin1 ubiquitination degradation. Together all, the results suggested that TRIM11 may be an oncogene in lymphomas, which involving the activation of the β-catenin signaling and the ubiquitination degradation of Axin1. Show less

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (p Show less

To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies. Show less

Lung cancer is a common malignant neoplasm that is prone to distant metastasis. Gastrointestinal metastasis from lung cancer is rather rare no matter what stage. Herein, we presented a case of pulmonary adenocarcinoma six months after thoracoscopic Lobectomy isolated metastasis to sigmoid colon. Then the patient underwent radical resection of metastatic tumors of sigmoid colon. The pathologic morphology and immunohistochemistry of lung adenocarcinoma is highly consistent with the sigmoid colon tumor and their gene profiles are likely similar expect for an AXIN1 mutation in primary tumor and not in the metastatic lesion. Show less