1,721,053 research outputs found
Cooperation between ZEB2 and Sp1 promotes cancer cell survival and angiogenesis during metastasis through induction of survivin and VEGF
No full textEpithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion and metastasis. During EMT, epithelial cells undergo molecular changes to acquire mesenchymal phenotypes, which are mediated by EMT-inducing transcription factors. Previously, we showed that ZEB2 cooperates with the transcription factor Sp1 to function as a transcriptional activator of vimentin, integrin a5, and cadherin-11, which promotes cancer cell invasion. We hypothesized that ZEB2, through cooperation with Sp1, would mediate diverse cellular functions beyond EMT and invasion during metastasis. ZEB2 upregulated the expression of Sp1-regulated genes such as survivin, bcl-2, cyclin D1, and vascular endothelial growth factor in an Sp1- dependent manner, resulting in increased cancer cell survival and proliferation and endothelial cell activation in vitro, and increased circulating tumor cell survival and tumor angiogenesis in vivo. In addition, Sp1 enhanced ZEB2 stability, suggesting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data showed that ZEB2 expression was positively associated with Sp1 expression, and that the expression of both of these factors had prognostic significance for predicting survival in cancer patients. This study suggests that invasion is linked to cancer cell survival and angiogenesis by ZEB2 during cancer progression, and increases our understanding of the pathways via which EMT-inducing transcription factors regulate the complex process of metastasis
Gas6 induces cancer cell migration and epithelial-mesenchymal transition through upregulation of MAPK and Slug
No full textBinding of Gas6 to Axl (Gas6/Axl axis) alters cellular functions, including migration, invasion, proliferation, and survival. However, the molecular mechanisms underlying Gas6-mediated cell migration remain poorly understood. In this study, we found that Gas6 induced the activation of JNK and ERK1/2 signaling in cancer cells expressing Axl, resulting in the phosphorylation of activator protein-1 (AP-1) transcription factors c-Jun and ATF-2, and induction of Slug. Depletion of c-Jun or ATF-2 by siRNA attenuated the Gas6-induced expression of Slug. Slug expression was required for cell migration and E-cadherin reduction/vimentin induction induced by Gas6. These results suggest that Gas6 induced cell migration via Slug upregulation in JNK- and ERK1/2-dependent mechanisms. These data provide an important insight into the molecular mechanisms mediating Gas6-induced cell migration.open
A nontoxic biocompatible nanocomposite comprising black phosphorus with Au–γ-Fe(2)O(3) nanoparticles
No full textBlack phosphorus (BP) has emerged as the latest 2D material within the post-graphene scenario, which can be used for various biomedical applications. In this study, we reported a promising nanocomposite material, which could be assembled with Au nanoparticles and γ-Fe(2)O(3) nanoparticles on BP nanosheets (AIB), and studied its biocompatibility that promises to be useful for various biomedical applications. The synthesis of the Au–γ-Fe(2)O(3) nanomaterial was attained through low-temperature solution synthesis and the exfoliation of BP nanosheets was performed through a liquid ultrasonication process. The individual components were then composited by ultrasonication and stirring. X-ray diffraction and transmission electron microscopic analyses confirmed the existence of Au and γ-Fe(2)O(3) nanoparticles (NPs) assembled over BP nanosheets. Moreover, the surface chemical composition and valence state of the elements present in the AIB nanocomposite were evaluated with the help of an X-ray photoelectron spectroscopy study. The AIB nanocomposite exhibited excellent biocompatibility with HCT-15 cells after evaluating through WST assay. Therefore, the excellent biocompatible nature of this BP nanocomposite could be beneficial for various potential biomedical applications
ZEB2 upregulates integrin α5 expression through cooperation with Sp1 to induce invasion during epithelial-mesenchymal transition of human cancer cells
No full textEpithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion, metastasis, embryonic development and wound healing. ZEB2 is a transcription factor involved in EMT that represses E-cadherin transcription. Although E-cadherin downregulation is a major event during EMT and tumor progression, E-cadherin reduction is probably not sufficient for full invasiveness. The mechanisms by which E-cadherin transcriptional repressors induce mesenchymal genes during EMT remain largely unknown. Here, we investigated the role of ZEB2 in the induction of integrin α5 during cancer EMT and its underlying mechanism. In human cancer cells, ZEB2 was found to directly upregulate integrin α5 transcription in a manner that is independent of the regulation of E-cadherin expression. Conversely, depletion of ZEB2 by small interfering RNA suppressed integrin α5 expression, leading to reduced invasion. Suppression of integrin α5 inhibited cancer cell invasion, suggesting an important role for integrin α5 in cancer progression. Furthermore, ZEB2 was found to activate the integrin α5 and vimentin promoters by interacting with and activating the transcription factor Sp1, suggesting that cooperation between ZEB2 and Sp1 represents a novel mechanism of mesenchymal gene activation during EMT. These findings increase our understanding of the pathways beyond E-cadherin reduction that regulate mesenchymal gene expression during EMT and cancer progression.open
TMEM52B suppression promotes cancer cell survival and invasion through modulating E-cadherin stability and EGFR activity
No full textBackground: TMEM52B is a novel gene broadly expressed in a variety of normal human tissues. However, the biological function of TMEM52B expression in cancer is largely unknown.
Methods: The effects of TMEM52B on tumor growth and metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. Clinical datasets from KmPlotter and The Cancer Genome Atlas (TCGA) were analyzed in relation to TMEM52B expression and function.
Results: Suppression of TMEM52B in colon cancer cells promoted cancer cell epithelial-mesenchymal transition (EMT), invasion, and survival in vitro. Similarly, in vivo studies showed increased tumor growth and circulating tumor cell survival (early metastasis). ERK1/2, JNK, and AKT signaling pathways were involved in TMEM52B suppression-induced invasiveness and cell survival. TMEM52B suppression promoted activation and internalization of epidermal growth factor receptor (EGFR) with enhanced downstream signaling activity, leading to enhanced cell survival and invasion. In addition, TMEM52B suppression reduced E-cadherin stability, likely due to a reduced association between it and E-cadherin, which led to enhanced β-catenin transcriptional activity. Concomitantly, TMEM52B suppression promoted generation of soluble E-cadherin fragments, contributing to the activation of EGFR. Clinical data showed that high TMEM52B expression correlated with increased patient survival in multiple types of cancer, including breast, lung, kidney, and rectal cancers, and suggested a correlation between TMEM52B and E-cadherin.
Conclusions: These findings suggest that TMEM52B is a novel modulator of the interplay between E-cadherin and EGFR. It is possible that TMEM52B functions as a tumor-suppressor that could potentially be used as a novel prognostic marker for cancer.
Fc fusion to Glucagon-like peptide-1 inhibits degradation by human DPP-IV, increasing its half-life in serum and inducing a potent activity for human GLP-1 receptor activation
No full textThe short in vivo half-life of GLP-1 prevents it from being used clinically. This short half-life occurs because GLP-1 is rapidly degraded by dipeptidyl peptidases such as DPP-IV. To overcome this obstacle, a GLP-1/Fc was constructed and evaluated to determine if it was degraded by DPP-IV and in serum. When the degradation of GLP-1/Fc by human DPP-IV and rabbit serum was compared with that of GLP-1 it was found to be reduced by approximately 5- and 4-fold, respectively. Furthermore, GLP-1/Fc showed a potent activity for human GLP-1 receptor activation (EC50 approximately 6 nM). Taken together, these results indicate that GLP-1/Fc may have an extended half-life in vivo that occurs as a result of inhibition of degradation by human DPP-IV. Due to the extended half life, GLP-1/Fc may be useful for clinical treatments.open
Twist1 and AP-1 cooperatively upregulate integrin α5 expression to induce invasion and the epithelial-mesenchymal transition
No full textEpithelial-mesenchymal transition (EMT) is an important process implicated in tumor invasion and metastasis. Twist1 is a transcription factor that induces EMT, including E-cadherin suppression and cancer cell migration and invasion; hence it promotes cancer metastasis. Twist1 directly or indirectly regulates the expression of various genes and cellular functions involved in cancer progression. However, the underlying mechanisms remain largely unknown. In this study, we investigated the molecular basis for Twist1-mediated invasion and EMT. In human cancer cells, Twist1 was found to directly upregulate transcription of the mesenchymal gene integrin α5 in an E-box-independent, but activating protein-1 (AP-1) element-dependent, manner. Twist1 activated the integrin α5 promoter by interacting with and activating the transcription factor AP-1, composed of c-Jun and activating transcription factor-2 (ATF-2); it also enhanced the nuclear presence of ATF-2. AP-1 was critical for Twist1-induced cancer cell invasion, primarily through the induction of integrin α5, which activated c-Jun N-terminal kinase and focal adhesion kinase-signaling activities. Using data from The Cancer Genome Atlas, we found that Twist1 expression positively correlates with integrin α5 expression in human colorectal cancers. These findings suggest that cooperation between Twist1 and AP-1 represents a novel mechanism for EMT and tumor invasiveness. This study supports further investigation into the molecular basis underlying the diverse Twist1-mediated functions that occur during tumor progression.open
Membrane Proteins Involved in Epithelial-Mesenchymal Transition and Tumor Invasion: Studies on TMPRSS4 and TM4SF5
Full text linkThe epithelial-mesenchymal transition (EMT) is one mechanism by which cells with mesenchymal features can be generated and is a fundamental event in morphogenesis. Recently, invasion and metastasis of cancer cells from the primary tumor are now thought to be initiated by the developmental process termed the EMT, whereby epithelial cells lose cell polarity and cell-cell interactions, and gain mesenchymal phenotypes with increased migratory and invasive properties. The EMT is believed to be an important step in metastasis and is implicated in cancer progression, although the influence of the EMT in clinical specimens has been debated. This review presents the recent results of two cell surface proteins, the functions and underlying mechanisms of which have recently begun to be demonstrated, as novel regulators of the molecular networks that induce the EMT and cancer progression
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