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Publication
Journal: FASEB Journal
February/23/2004
Abstract
Skeletal muscle differentiation is a complex, highly coordinated process that relies on precise temporal gene expression patterns. To better understand this cascade of transcriptional events, we used expression profiling to analyze gene expression in a 12-day time course of differentiating C2C12 myoblasts. Cluster analysis specific for time-ordered microarray experiments classified 2895 genes and ESTs with variable expression levels between proliferating and differentiating cells into 22 clusters with distinct expression patterns during myogenesis. Expression patterns for several known and novel genes were independently confirmed by real-time quantitative RT-PCR and/or Western blotting and immunofluorescence. MyoD and MEF family members exhibited unique expression kinetics that were highly coordinated with cell-cycle withdrawal regulators. Among genes with peak expression levels during cell cycle withdrawal were Vcam1, Itgb3, Itga5, Vcl, as well as Ptger4, a gene not previously associated with the process of myogenesis. One interesting uncharacterized transcript that is highly induced during myogenesis encodes several immunoglobulin repeats with sequence similarity to titin, a large sarcomeric protein. These data sets identify many additional uncharacterized transcripts that may play important functions in muscle cell proliferation and differentiation and provide a baseline for comparison with C2C12 cells expressing various mutant genes involved in myopathic disorders.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
December/6/2009
Abstract
Adult human mesenchymal stromal cells (hMSCs) have the potential to differentiate into chondrogenic, adipogenic, or osteogenic lineages, providing a potential source for tissue regeneration. An important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptome analysis, we found that integrin alpha5 (ITGA5) expression is up-regulated during dexamethasone-induced osteoblast differentiation of hMSCs. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers and in vitro osteogenesis of hMSCs. Down-regulation of endogenous ITGA5 using specific shRNAs blunted osteoblast marker gene expression and osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by ITGA5 was mediated by activation of focal adhesion kinase/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of endogenous ITGA5 using agonists such as a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. Importantly, we demonstrated that hMSCs engineered to overexpress ITGA5 exhibited a marked increase in their osteogenic potential in vivo. Taken together, these findings not only reveal that ITGA5 is required for osteoblast differentiation of adult hMSCs but also provide a targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs. This may be used for tissue regeneration in bone disorders where the recruitment or capacity of hMSCs is compromised.
Publication
Journal: Developmental Cell
July/11/2005
Abstract
Boundary formation and epithelialization are crucial processes in the morphological segmentation of vertebrate somites. By a genetic screening procedure with zebrafish, we identified two genes, integrinalpha5 (itga5) and fibronectin (fn), required for these processes. Fibronectin proteins accumulate at somite boundaries in accordance with epithelialization of the somites. Both Fibronectin accumulation and the epithelialization are dependent on itga5, which is expressed in the most medial part of somites. Although somite boundaries are initially formed, but not maintained, in the anterior trunk of the mutant embryos deficient in either gene, their maintenance is defective at all axial levels of embryos deficient for both of these genes. Therefore, Integrinalpha5-directed assembly of Fibronectin appears critical for epithelialization and boundary maintenance of somites. Furthermore, with an additional deficiency in ephrin-B2a, the segmental defect in itga5 or fn mutant embryos is expanded posteriorly, indicating that both Integrin-Fibronectin and Eph-Ephrin systems function cooperatively in maintaining somite boundaries.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
July/8/2004
Abstract
Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.
Publication
Journal: Cancer Research
July/21/2010
Abstract
miR-31 inhibits breast cancer metastasis via the pleiotropic suppression of a cohort of prometastatic target genes that include integrin alpha(5) (ITGA5), radixin (RDX), and RhoA. We previously showed that the concomitant overexpression of ITGA5, RDX, and RhoA was capable of overriding the antimetastatic effects of ectopically expressed miR-31 in vivo. However, these prior studies failed to investigate whether the combined suppression of the endogenous mRNAs encoding these three proteins recapitulated the in vivo consequences of miR-31 expression on metastasis. We show here that short hairpin RNA-mediated concurrent downregulation of ITGA5, RDX, and RhoA is sufficient to phenocopy the full spectrum of described influences of miR-31 on metastasis in vivo, including the effects of this microRNA (miRNA) on local invasion, early post-intravasation events, and metastatic colonization. These findings provide mechanistic insights into the metastatic process and have implications about the importance of pleiotropy for the biological actions of miRNAs.
Publication
Journal: FASEB Journal
April/25/2013
Abstract
Breast cancer is often fatal during its metastatic dissemination. To unravel the role of microRNAs (miRs) during malignancy, we analyzed miR expression in 77 primary breast carcinomas and identified 16 relapse-associated miRs that correlate with survival and/or distinguish tumor subtypes in different datasets. Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells. Our findings reveal the importance of the identified 16 miRs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progression.
Publication
Journal: Development (Cambridge)
November/27/2011
Abstract
Fibronectin (FN) is a major component of the extracellular matrix and functions in cell adhesion, cell spreading and cell migration. In the retina, FN is transiently expressed and assembled on astrocytes (ACs), which guide sprouting tip cells and deposit a provisional matrix for sprouting angiogenesis. The precise function of FN in retinal angiogenesis is largely unknown. Using genetic tools, we show that astrocytes are the major source of cellular FN during angiogenesis in the mouse retina. Deletion of astrocytic FN reduces radial endothelial migration during vascular plexus formation in a gene dose-dependent manner. This effect correlates with reduced VEGF receptor 2 and PI3K/AKT signalling, and can be mimicked by selectively inhibiting VEGF-A binding to FN through intraocular injection of blocking peptides. By contrast, AC-specific replacement of the integrin-binding RGD sequence with FN-RGE or endothelial deletion of itga5 shows little effect on migration and PI3K/AKT signalling, but impairs filopodial alignment along AC processes, suggesting that FN-integrin α5β1 interaction is involved in filopodial adhesion to the astrocytic matrix. AC FN shares its VEGF-binding function and cell-surface distribution with heparan-sulfate (HS), and genetic deletion of both FN and HS together greatly enhances the migration defect, indicating a synergistic function of FN and HS in VEGF binding. We propose that in vivo the VEGF-binding properties of FN and HS promote directional tip cell migration, whereas FN integrin-binding functions to support filopodia adhesion to the astrocytic migration template.
Publication
Journal: Cell Death and Differentiation
August/14/2013
Abstract
Many cellular responses during development are regulated by interactions between integrin receptors and extracellular matrix proteins (ECMPs). Although the majority of recent studies in human embryonic stem cell (hESC) differentiation have focused on the role of growth factors, such as FGF, TGFβ, and WNT, relatively little is known about the role of ECMP-integrin signaling in this process. Moreover, current strategies to direct hESC differentiation into various lineages are inefficient and have yet to produce functionally mature cells in vitro. This suggests that additional factors, such as ECMPs, are required for the efficient differentiation of hESCs. Using a high-throughput multifactorial cellular array technology, we investigated the effect of hundreds of ECMP combinations and concentrations on differentiation of several hPSC lines to definitive endoderm (DE), an early embryonic cell population fated to give rise to internal organs such as the lung, liver, pancreas, stomach, and intestine. From this screen we identified fibronectin (FN) and vitronectin (VTN) as ECMP components that promoted DE differentiation. Analysis of integrin expression revealed that differentiation toward DE led to an increase in FN-binding integrin α5 (ITGA5) and VTN-binding integrin αV (ITGAV). Conditional short hairpin RNA-mediated knockdown of ITGA5 and ITGAV disrupted hESC differentiation toward DE. Finally, fluorescence-based cell sorting for ITGA5 and ITGAV significantly enriched cells with gene expression signatures associated with DE, demonstrating that these cell surface proteins permit isolation and enrichment of DE from hESCs. These data provide evidence that FN and VTN promote endoderm differentiation of hESCs through interaction with ITGA5 and ITGAV, and that ECMP-integrin interactions are required for hESC differentiation into functionally mature cells.
Publication
Journal: American Journal of Pathology
March/24/2014
Abstract
Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin α5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.
Publication
Journal: Development (Cambridge)
September/17/2006
Abstract
Development of the facial skeleton depends on interactions between intrinsic factors in the skeletal precursors and extrinsic signals in the facial environment. Hox genes have been proposed to act cell-intrinsically in skeletogenic cranial neural crest cells (CNC) for skeletal pattern. However, Hox genes are also expressed in other facial tissues, such as the ectoderm and endoderm, suggesting that Hox genes could also regulate extrinsic signalling from non-CNC tissues. Here we study moz mutant zebrafish in which hoxa2b and hoxb2a expression is lost and the support skeleton of the second pharyngeal segment is transformed into a duplicate of the first-segment-derived jaw skeleton. By performing tissue mosaic experiments between moz(-) and wild-type embryos, we show that Moz and Hox genes function in CNC, but not in the ectoderm or endoderm, to specify the support skeleton. How then does Hox expression within CNC specify a support skeleton at the cellular level? Our fate map analysis of skeletal precursors reveals that Moz specifies a second-segment fate map in part by regulating the interaction of CNC with the first endodermal pouch (p1). Removal of p1, either by laser ablation or in the itga5(b926) mutant, reveals that p1 epithelium is required for development of the wild-type support but not the moz(-) duplicate jaw-like skeleton. We present a model in which Moz-dependent Hox expression in CNC shapes the normal support skeleton by instructing second-segment CNC to undergo skeletogenesis in response to local extrinsic signals.
Publication
Journal: Cancer Research
April/20/2011
Abstract
Metastatic breast cancer remains a lethal disease with poorly understood molecular mechanisms. Steroid receptor coactivator-1 (SRC-1 or NCOA1) is overexpressed in a subset of breast cancers with poor prognosis. It potentiates gene expression by serving as a coactivator for nuclear receptors and other transcription factors. We previously reported that SRC-1 promotes breast cancer metastasis without affecting primary mammary tumor formation. Herein, we found that SRC-1 deficiency in mouse and human breast cancer cells substantially reduced cell adhesion and migration capabilities on fibronectin and significantly extended the time of focal adhesion disassembly and reassembly. In agreement with this phenotype, SRC-1 expression positively correlated with integrin α(5) (ITGA5) expression in estrogen receptor-negative breast tumors whereas SRC-1 deficiency decreased ITGA5 expression. Furthermore, ITGA5 reduction in SRC-1-deficient/insufficient breast cancer cells or knockdown of ITGA5 in SRC-1-expressing breast cancer cells was associated with a disturbed integrin-mediated signaling. Critical downstream changes included reduced phosphorylation and/or dampened activation of focal adhesion kinase, paxillin, Rac1, and Erk1/2 during cell adhesion. Finally, we found that SRC-1 enhanced ITGA5 promoter activity through an AP-1 (activator protein)-binding site proximal to the transcriptional initiation site; both SRC-1 and c-Jun were recruited to this promoter region in breast cancer cells. These results show that SRC-1 can promote breast cancer metastasis by directly enhancing ITGA5 expression and thus promoting ITGA5-mediated cell adhesion and migration. Therefore, targeting ITGA5 in SRC-1-positive breast cancers may result in inhibition of SRC-1-promoted breast cancer metastasis.
Publication
Journal: Cancer Research
September/14/2018
Abstract
miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivoIn vitro, miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell-conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation (IL8, IL11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11), and invasiveness (CTGF, ITGA5, ITGB3) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention.Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer. Cancer Res; 78(18); 5259-73. ©2018 AACR.
Publication
Journal: Journal of Experimental and Clinical Cancer Research
September/12/2019
Abstract
Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA in glioma and elucidate how circRNA acts.Real-time PCR was used to examine the expression of circPTN in glioma tissues and normal brain tissues (NBT). Assays of dual- luciferase reporter system, biotin label RNA pull-down and FISH were used to determine that circPTN could sponge miR-145-5p and miR-330-5p. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Cell counting Kit-8 (CCK8), EdU assay and flow cytometry were used to investigate proliferation and cell cycle. Intracranial xenograft was established to determine how circPTN impacts in vivo. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs).We demonstrated circPTN was significantly higher expression in glioma tissues and glioma cell lines, compared with NBT and HEB (human astrocyte). In gain- and loss-of-function experiments, circPTN significantly promoted glioma growth in vitro and in vivo. Furthermore, we performed dual-luciferase reporter assays and RNA pull-down assays to verify that circPTN acts through sponging miR-145-5p and miR-330-5p. Increasing expression of circPTN rescued the inhibition of proliferation and downregulation of SOX9/ITGA5 in glioma cells by miR-145-5p/miR-330-5p. In addition, we found that circPTN promoted self-renewal and increased the expression of stemness markers (Nestin, CD133, SOX9, and SOX2) via sponging miR-145-5p. Moreover, this regulation was disappeared when circPTN binding sites in miR-145-5p were mutated.Our results suggest that circPTN is an oncogenic factor that acts by sponging miR-145-5p/miR-330-5p in glioma.
Publication
Journal: BMC Cell Biology
November/2/2010
Abstract
BACKGROUND
The potential of mesenchymal stromal cells (MSCs) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors that trigger osteoblast differentiation in MSCs is therefore critical to promote the osteogenic potential of human MSCs. In this study, we used microarray analysis to identify signalling molecules that promote osteogenic differentiation in human bone marrow stroma derived MSCs.
RESULTS
Microarray analysis and validation experiments showed that the expression of IGF2 and IGFBP2 was increased together with integrin alpha5 (ITGA5) during dexamethasone-induced osteoblast differentiation in human MSCs. This effect was functional since we found that IGF2 and IGFBP2 enhanced the expression of osteoblast phenotypic markers and in vitro osteogenic capacity of hMSCs. Interestingly, we showed that downregulation of endogenous ITGA5 using specific shRNA decreased IGF2 and IGFBP2 expression in hMSCs. Conversely, ITGA5 overexpression upregulated IGF2 and IGFBP2 expression in hMSCs, which indicates tight crosstalks between these molecules. Consistent with this concept, activation of endogenous ITGA5 using a specific antibody that primes the integrin, or a peptide that specifically activates ITGA5 increased IGF2 and IGFBP2 expression in hMSCs. Finally, we showed that pharmacological inhibition of FAK/ERK1/2-MAPKs or PI3K signalling pathways that are enhanced by ITGA5 activation, blunted IGF2 and IGFBP2 expression in hMSCs.
CONCLUSIONS
The results show that ITGA5 is a key mediator of IGF2 and IGFBP2 expression that promotes osteoblast differentiation in human MSCs, and reveal that crosstalks between ITGA5 and IGF2/IGFBP2 signalling are important mechanisms that trigger osteogenic differentiation in human bone marrow derived mesenchymal stromal cells.
Publication
Journal: Genome Medicine
January/13/2015
Abstract
BACKGROUND
Improved usage of the repertoires of pancreatic ductal adenocarcinoma (PDAC) profiles is crucially needed to guide the development of predictive and prognostic tools that could inform the selection of treatment options.
METHODS
Using publicly available mRNA abundance datasets, we performed a large retrospective meta-analysis on 466 PDAC patients to discover prognostic gene signatures. These signatures were trained on two clinical cohorts (n = 70), and validated on four independent clinical cohorts (n = 246). Further validation of the identified gene signature was performed using quantitative real-time RT-PCR.
RESULTS
We identified 225 candidate prognostic genes. Using these, a 36-gene signature was discovered and validated on fully independent clinical cohorts (hazard ratio (HR) = 2.06, 95% confidence interval (CI) = 1.51 to 2.81, P = 3.62 × 10(-6), n = 246). This signature serves as a good alternative prognostic stratification marker compared to tumour grade (HR = 2.05, 95% CI = 1.45 to 2.88, P = 3.18 × 10(-5)) and tumour node metastasis (TNM) stage (HR = 1.13, 95% CI = 0.66 to 1.94, P = 0.67). Upon multivariate analysis with adjustment for TNM stage and tumour grade, the 36-gene signature remained an independent prognostic predictor of clinical outcome (HR = 2.21, 95% CI = 1.17 to 4.16, P = 0.01). Univariate assessment revealed higher expression of ITGA5, SEMA3A, KIF4A, IL20RB, SLC20A1, CDC45, PXN, SSX3 and TMEM26 was correlated with shorter survival while B3GNT1, NOSTRIN and CADPS down-regulation was associated with poor outcome.
CONCLUSIONS
Our 36-gene classifier is able to prognosticate PDAC independent of patient cohort and microarray platforms. Further work on the functional roles, downstream events and interactions of the signature genes is likely to reveal true molecular candidates for PDAC therapeutics.
Publication
Journal: Journal of Urology
May/18/2016
Abstract
Renal cell carcinoma is the most common highly metastatic kidney malignancy. Adhesion has a crucial role in the metastatic process. TGF (transforming growth factor)-β1 is a pleiotropic cytokine that influences cancerous transformation. We hypothesized that 1) changes in the expression of adhesion related genes may influence survival rate of patients with renal cell carcinoma and 2) TGF-β1 may contribute to changed expression of adhesion related genes.
Two-step quantitative real-time polymerase chain reaction arrays were used to analyze the expression of adhesion related genes in 77 tumors and matched pair controls. The prognostic significance of genes was evaluated in TCGA (The Cancer Genome Atlas) data on 468 patients with renal cell carcinoma. Quantitative real-time polymerase chain reaction and Western blot were applied for TGF-β1 analysis. TGF-β1 mediated regulation of gene expression was analyzed by TGF-β1 supplementation of Caki-2 cells and quantitative real-time polymerase chain reaction.
The expression of 19 genes related to adhesion and extracellular matrix remodeling was statistically significantly disturbed in renal cell carcinoma compared with controls. The 10-gene expression signature (COL1A1, COL5A1, COL11A1, FN1, ICAM1, ITGAL, ITGAM, ITGB2, THBS2 and TIMP1) correlated with poor survival (HR 2.85, p = 5.7e-10). TGF-β1 expression was 22 times higher in renal cell carcinoma than in controls (p <0.0001). TGF-β1 induced expression of TGFBI, COL1A1, COL5A1, COL8A1, FN1, ITGA5, ITGAM and TIMP1 in a renal cell carcinoma derived cell line.
Disturbed expression of genes involved in adhesion and extracellular matrix remodeling develops early during renal cell carcinoma carcinogenesis and correlates with poor survival. TGF-β1 contributes to changed expression of extracellular matrix and adhesion related genes. Bioinformatic analysis performed on a broad panel of cancers of nonkidney origin suggests that disturbed expression of genes related to extracellular matrix and adhesion may be a universal feature of cancerous progression.
Publication
Journal: Journal of Cellular Biochemistry
April/23/2018
Abstract
Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.
Publication
Journal: American Journal of Pathology
January/24/2011
Abstract
Endothelial dysfunction is involved in vascular complications of obstructive sleep apnea (OSA). In this study, circulating microparticles (MPs) from patients with OSA-induced nocturnal desaturations were characterized and their effects on endothelial function were evaluated. Two age-matched groups of patients undergoing polysomnography for OSA were compared: 35 desaturators with a 3% oxyhemoglobin desaturation index (ODI)>> or = 10 events per hour of sleep and 27 nondesaturators with ODI <10 events per hour. MPs were characterized by flow cytometry and then either used to treat in vitro human endothelial cells or to study endothelial function in mice. Circulating MPs did not differ between groups, but MPs from granulocytes and activated leukocytes (CD62L(+)) were found at higher levels in desaturators. In vitro, MPs from desaturators reduced endothelial nitric oxide (NO) production by enhancing phosphorylation of endothelial NO synthase at the site of inhibition and expression of caveolin-1. CD62L(+) MPs positively correlated with ODI. Endothelial NO production negatively correlated with both CD62L(+) MPs and ODI. MPs from desaturators increased expression of endothelial adhesion molecules including E-selectin, ICAM-1 and ITGA5, and cyclooxygenase 2. Moreover, injection of MPs from desaturators into mice impaired endothelium-dependent relaxation in aorta and flow-induced dilation in small mesenteric arteries. This study demonstrates an association between endothelial dysfunction and increased circulating levels of CD62L(+) MPs. This may initiate atherogenic processes in patients with OSA and severe nighttime hypoxia.
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Publication
Journal: PLoS ONE
November/24/2008
Abstract
BACKGROUND
Numerous studies were performed to illuminate mechanisms of tumorigenesis and metastases from gene expression profiles of Head and Neck Squamous Cell Carcinoma (HNSCC). The objective of this review is to conduct a network-based meta-analysis to identify the underlying biological signatures of the HNSCC transcriptome.
RESULTS
We included 63 HNSCC transcriptomic studies into three specific categories of comparisons: Pre, premalignant lesions v.s. normal; TvN, primary tumors v.s. normal; and Meta, metastatic or invasive v.s. primary tumors. Reported genes extracted from the literature were systematically analyzed. Participation of differential gene activities across three progressive stages deciphered the evolving nature of HNSCC. In total, 1442 genes were verified, i.e. reported at least twice, with ECM1, EMP1, CXCL10 and POSTN shown to be highly reported across all three stages. Knowledge-based networks of the HNSCC transcriptome were constructed, demonstrating integrin signaling and antigen presentation pathways as highly enriched. Notably, functional estimates derived from topological characteristics of integrin signaling networks identified such important genes as ITGA3 and ITGA5, which were supported by findings of invasiveness in vitro. Moreover, we computed genome-wide probabilities of reporting differential gene activities for the Pre, TvN, and Meta stages, respectively. Results highlighted chromosomal regions of 6p21, 19p13 and 19q13, where genomic alterations were shown to be correlated with the nodal status of HNSCC.
CONCLUSIONS
By means of a systems-biology approach via network-based meta-analyses, we provided a deeper insight into the evolving nature of the HNSCC transcriptome. Enriched canonical signaling pathways, hot-spots of transcriptional profiles across the genome, as well as topologically significant genes derived from network analyses were highlighted for each of the three progressive stages, Pre, TvN, and Meta, respectively.
Publication
Journal: Oncology
February/20/2013
Abstract
OBJECTIVE
To evaluate the relationship between the expression of the extracellular matrix (ECM) genes SPARC, SPP1, FN1, ITGA5 and ITGAV and the histopathologic parameters of neoplastic progression and colorectal carcinoma (CRC) dissemination.
METHODS
A retrospective study was conducted in 114 patients with stage I-IV CRC who underwent primary tumor resection. Quantitative real-time PCR and immunohistochemistry (IHC) assays were performed in samples obtained from the primary tumors. The correlation between the expression of these markers and the expression of p53, Bcl-2, Ki67, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor was assessed with the Spearman coefficient (r).
RESULTS
The ITGAV gene was found to be significantly amplified in tumors with positive perineural invasion (p = 0.028). Expression of the SPARC, SPP1, FN1, ITGA5 and ITGAV genes did not correlate with TNM staging. A direct relationship between ITGAV and EGFR expression (r = 0.774; p < 0.001) was observed by IHC.
CONCLUSIONS
ECM gene expression did not correlate with classical prognostic factors for CRC, but overexpression of the ITGAV gene and protein was correlated with an increased risk of perineural invasion. The relationship between ITGAV and EGFR expression suggests the possibility of crosstalk in this signal pathway.
Publication
Journal: Stem cell reviews
April/27/2011
Abstract
Genostem (acronym for "Adult mesenchymal stem cells engineering for connective tissue disorders. From the bench to the bed side") has been an European consortium of 30 teams working together on human bone marrow Mesenchymal Stem Cell (MSC) biological properties and repair capacity. Part of Genostem activity has been dedicated to the study of basic issues on undifferentiated MSCs properties and on signalling pathways leading to the differentiation into 3 of the connective tissue lineages, osteoblastic, chondrocytic and tenocytic. We have evidenced that native bone marrow MSCs and stromal cells, forming the niche of hematopoietic stem cells, were the same cellular entity located abluminally from marrow sinus endothelial cells. We have also shown that culture-amplified, clonogenic and highly-proliferative MSCs were bona fide stem cells, sharing with other stem cell types the major attributes of self-renewal and of multipotential priming to the lineages to which they can differentiate (osteoblasts, chondrocytes, adipocytes and vascular smooth muscle cells/pericytes). Extensive transcription profiling and in vitro and in vivo assays were applied to identify genes involved in differentiation. Thus we have described novel factors implicated in osteogenesis (FHL2, ITGA5, Fgf18), chondrogenesis (FOXO1A) and tenogenesis (Smad8). Another part of Genostem activity has been devoted to studies of the repair capacity of MSCs in animal models, a prerequisite for future clinical trials. We have developed novel scaffolds (chitosan, pharmacologically active microcarriers) useful for the repair of both bone and cartilage. Finally and most importantly, we have shown that locally implanted MSCs effectively repair bone, cartilage and tendon.
Publication
Journal: Journal of Experimental Medicine
February/2/2019
Abstract
High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor-stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.
Publication
Journal: PeerJ
December/20/2018
Abstract
Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective approaches to diagnose and treat cancer. In this study, we aim to identify the hub genes and investigate the underlying molecular mechanisms of GC.To explore potential therapeutic targets for GC,three expression profiles (GSE54129, GSE33651, GSE81948) of the genes were extracted from the Gene Expression Omnibus (GEO) database. The GEO2R online tool was applied to screen out differentially expressed genes (DEGs) between GC and normal gastric samples. Database for Annotation, Visualization and Integrated Discovery was applied to perform Gene Ontology (GO) and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network of these DEGs was constructed using a STRING online software. The hub genes were identified by the CytoHubba plugin of Cytoscape software. Then, the prognostic value of these identified genes was verified by gastric cancer database derived from Kaplan-Meier plotter platform.A total of 85 overlapped upregulated genes and 44 downregulated genes were identified. The majority of the DEGs were enriched in extracellular matrix organization, endodermal cell differentiation, and endoderm formation. Moreover, five KEGG pathways were significantly enriched, including ECM-receptor interaction, amoebiasis, AGE-RAGE signaling pathway in diabetic complications, focal adhesion, protein digestion and absorption. By combining the results of PPI network and CytoHubba, a total of nine hub genes including COL1A1, THBS1, MMP2, CXCL8, FN1, TIMP1, SPARC, COL4A1, and ITGA5 were selected. The Kaplan-Meier plotter database confirmed that overexpression levels of these genes were associated with reduced overall survival, except for THBS1 and CXCL8.Our study suggests that COL1A1, MMP2, FN1, TIMP1, SPARC, COL4A1, and ITGA5 may be potential biomarkers and therapeutic targets for GC. Further study is needed to assess the effect of THBS1 and CXCL8 on GC.
Publication
Journal: PeerJ
November/13/2018
Abstract
UNASSIGNED
Gastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world. In the current study, we aim to identify the hub genes and uncover the molecular mechanisms of GC.
UNASSIGNED
The expression profiles of the genes and the miRNAs were extracted from the Gene Expression Omnibus database. The identification of the differentially expressed genes (DEGs), including miRNAs, was performed by the GEO2R. Database for Annotation, Visualization and Integrated Discovery was used to perform GO and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network and miRNA-gene network were constructed using Cytoscape software. The hub genes were identified by the Molecular Complex Detection (MCODE) plugin, the CytoHubba plugin and miRNA-gene network. Then, the identified genes were verified by Kaplan-Meier plotter database and quantitative real-time PCR (qRT-PCR) in GC tissue samples.
UNASSIGNED
A total of three mRNA expression profiles (GSE13911, GSE79973 and GSE19826) were downloaded from the Gene Expression Omnibus (GEO) database, including 69, 20 and 27cases separately. A total of 120 overlapped upregulated genes and 246 downregulated genes were identified. The majority of the DEGs were enriched in extracellular matrix organization, collagen catabolic process, collagen fibril organization and cell adhesion. In addition, three KEGG pathways were significantly enriched, including ECM-receptor interaction, protein digestion and absorption, and the focal adhesion pathways. In the PPI network, five significant modules were detected, while the genes in the modules were mainly involved in the ECM-receptor interaction and focal adhesion pathways. By combining the results of MCODE, CytoHubba and miRNA-gene network, a total of six hub genes including COL1A2, COL1A1, COL4A1, COL5A2, THBS2 and ITGA5 were chosen. The Kaplan-Meier plotter database confirmed that higher expression levels of these genes were related to lower overall survival, except for COL5A2. Experimental validation showed that the rest of the five genes had the same expression trend as predicted.
UNASSIGNED
In conclusion, COL1A2, COL1A1, COL4A1, THBS2 and ITGA5 may be potential biomarkers and therapeutic targets for GC. Moreover, ECM-receptor interaction and focal adhesion pathways play significant roles in the progression of GC.
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