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Exosomes derived from GPC5-overexpressing human lung cancer cells inhibits tube formation and migration of hLECs via delivery of miR-26b A The heat map showed the differentially expressed miRNAs in exosomes derived from normal and GPC5-overexpressing human lung cancer cells. B Real-time PCR confirmed the elevated expression of miR-26b in GPC5-overexpressing human lung cancer cells and their secreted exosomes. C RT-PCR showed the efficiency of miR-26b depletion in normal and GPC5-overexpressing human lung cancer cells. D After 24-h incubation with exosomes derived from indicated human lung cancer cells, tube formation assay of hLECs was conducted. E After 24-h incubation with exosomes derived from indicated human lung cancer cells, wound healing assay of hLECs was conducted. F After 24-h incubation with exosomes derived from indicated human lung cancer cells, the VEGF concentration in the culture medium of hLECs was determined. Data were presented as means ± SEM, n = 3; statistical significance: *p < 0.05, **p < 0.01, ***p < 0.001.
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Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via...
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Treatment of metastatic breast cancer patients is challenging and remains a major underlying cause of female mortality. Understanding molecular alterations in tumor development is critical to identify novel biomarkers and targets for cancer diagnosis and therapy. One of the aberrant cancer expressions gaining recent research interest is gly...
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... Corroborating our findings, another study found lower GPC5 expression in LC tissues than adjacently noncancerous cells. The presence of GPC5 appears to suppress LC cell migration and invasion [37]. Additionally, it has been reported GPC5 possesses the capability to induce G1/S phase arrest in these cells, improving prognosis [38].These disparate associations underscore the intricate and multifaceted nature of hsa-miR-1270's role in cancer progression and prognosis. ...
... AHR has been shown to account for lung cancer carcinogenesis [43,44]. However, studies regarding its role in lung cancer metastasis have yielded conflicting conclusions [45]. It is noteworthy that AHR's pro-metastatic function has been substantiated in clinical contexts, where elevated AHR levels correlate positively with disease recurrence and distant metastasis in LUAD patients [23]. ...
Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.
... AhR/ARNT heterodimers transcriptionally upregulate CTDSP1. GPC5 overexpression impaired the lymph node metastasis of lung cancer cells in animal models [43]. ...
The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and “diametrically opposed” roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs.
... The name CTD is taken from the C-terminal domain (CTD) of RNA polymerase II (RNAPII) because CTD phosphatase 1 (CTDP1) can dephosphorylate the phosphorylated residues of the CTD of RNAPII [3]. There are seven CTDPs in the human genome, which consist of CTD phosphatase 1 (CTDP1) [4], CTD small phosphatase 1 (CTDSP1) [5], CTD small phosphatase 2 (CTDSP2) [6], CTD small phosphatase-like (CTDSPL) [7], CTD nuclear envelope phosphatase 1 (CTDNEP1) [8], CTD small phosphatase-like 2 (CTDSPL2) [9], and ubiquitin-like domain-containing CTD phosphatase 1 (UBLCP1) [10]. CTDP1's dephosphorylation results in the termination of RNAPII transcription and is necessary for cell survival [2]. ...
... Therefore, CTDNEP1 suppresses brain tumors by triggering MYC amplification and genomic instability. There are several articles showing the possibility of using CTD phosphatases as tumor suppressors [5,7,[57][58][59][60][61][62][63]. CTDSP1 has also been reported as a phosphatase of MYC Ser62 in liver cancers [59]. ...
C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly Dullard) is a member of the newly emerging protein phosphatases and has been recognized in neuronal cell tissues in amphibians. It contains the phosphatase domain in the C-terminal, and the sequences are conserved in various taxa of organisms. CTDNEP1 has several roles in novel biological activities such as neural tube development in embryos, nuclear membrane biogenesis, regulation of bone morphogenetic protein signaling, and suppression of aggressive medulloblastoma. The three-dimensional structure of CTDNEP1 and the detailed action mechanisms of CTDNEP1’s functions have yet to be determined for several reasons. Therefore, CTDNEP1 is a protein phosphatase of interest due to recent exciting and essential works. In this short review, we summarize the presented biological roles, possible substrates, interacting proteins, and research prospects of CTDNEP1.
... The miR-26b is located in the fourth intron region of CTDSP1 gene. Previous researches have revealed that decreased miR-26b expression correlates with the progression of numerous tumors, such as colorectal cancer [19], lung cancer [20], and breast cancer [21]. Another member of the miR-26b family, miR-26a, has been connected to the formation of NPC [22], but the involvement of miR-26b in NPC has yet to be reported. ...
To screen microRNAs (miRNAs) and analyze their role in the nasopharyngeal carcinoma (NPC) development through differential analysis and cytological validation of the nasopharyngeal carcinoma dataset. The Gene Expression Omnibus (GEO) database of NPC-related data were utilized to screen for differential miRNAs, downstream target genes and relevant pathways, and the relationships among them were verified by luciferase reporter assay and cell co-culture. To analyze the function of miRNAs and downstream target genes, a series of mimics, inhibitors or Small interfering RNAs (siRNAs) targeting the downstream target genes were transfected into NPC cells or normal epithelial cells by cell transfection techniques. Cell Counting Kit-8 (CCK8), Transwell, Enzyme-linked immunosorbent assay (ELISA) apoptosis, and western blotting were adopted to determine the changes in cell activity, invasiveness, and apoptosis after differential miRNA and target gene overexpression or downregulation. Differential analysis of miRNA dataset showed that the expression of miR-26b was significantly downregulated in NPC, in agreement with the validation results of nasopharyngeal carcinoma cell lines. And downregulation of miR-26b expression in normal nasopharyngeal epithelial cells transformed the cells to tumors. CEP135 was identified as the miR-26b downstream target gene by mRNA dataset analysis, and a luciferase reporter test revealed a direct targeting link between the two. Upregulation of CEP135 levels in nasopharyngeal cancer cell lines increased cell activity, accelerated cell migration, and inhibited apoptosis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that CEP135 exerted the above effects on cells via the NF-κB pathway, and co-culture with NF-κB pathway blockers reversed cell biological behavior to the level of the control group. MiR-26b downregulation leads to CEP135 overexpression and NF-κB pathway activation in NPC, which enhances proliferation, migration, and prevents apoptosis of nasopharyngeal carcinoma cells. Therefore, the study further clarifies the biological behavior mechanism of NPC and suggests new therapeutic options for NPC.
... GPC5 is a member of the heparin sulfate proteoglycan family and is attached to the exocytoplasmic face of the plasma membrane via a glycosylphosphatidylinositol linkage [18,19]. GPC5 participates in normal cell proliferation, division, growth and development [20,21] as well as the formation, proliferation, migration and invasion of tumor cells via the wingless integrated, Hedgehog and FGF signaling pathways ( Figure 1) [22][23][24][25]. Alterations in the locus and expression of GPC5 have been observed in a variety of human malignancies, including breast cancer [26], lymphoma [27] and prostate cancer [28], and this can affect prognosis. ...
Background: GPC5 rs2352028 is associated with the risk of lung cancer, but its relationship with lung cancer prognosis is unclear. Materials & methods: The authors collected blood samples from 888 patients with lung cancer and used a Cox proportional hazards model to analyze the association between prognosis and GPC5 polymorphism rs2352028. Results: GPC5 rs2352028 C > T was associated with a better prognosis. Patients with CT genotype had longer overall survival than those with CC genotype. Additionally, older and early-stage patients with CT + TT genotype had a lower risk of death than those with CC genotype. Conclusion: GPC5 rs2352028 C > T may play a protective role in patients with lung cancer and GPC5 rs2352028 may be a potential genetic marker for lung cancer prognosis.
... Furthermore, exosomes originating from GPC5-overexpressing lung cancer cells (GPC5-OE-originated exosomes) had an inhibitory action on LECs, reducing their generation and diffusion. The mechanism of action of miRNA-26b in LEC is related to the inhibition of the protein tyrosine kinase 2 (PTK2) 3 -UTR [58]. ...
Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes.
... Exosomes are membranous vesicles (30~150 nm) released by different cell types into the extracellular environment upon fusion of multivesicular bodies (MVB) with the plasma membrane [9,10]. Exosomes secreted by tumor cells can travel through the body fluids to deliver their contents (lipids, mRNAs, microRNAs, proteins or DNA) to the target cells without degradation [9,[11][12][13] thus regulating cancer progression, metastasis, organotropism, chemoresistance as well as inducing cancer cachexia [4,14,15]. In our previous study, we also found that microRNAs in exosomes secreted by murine C26 colon tumor cells could induce cancer cachexia by inducing Bcl-2mediated apoptosis in skeletal muscle. ...
Tumor-derived exosomes are emerging mediators of cancer cachexia. Clarifying the regulation of exosome biogenesis and finding possible targets for cancer cachexia therapy are important and necessary. In the present study, systemic analysis of the roles of STAT3 in controlling exosome biogenesis of murine C26 colon tumor cells and its contribution to the development of cancer cachexia is conducted. The genetic manipulation of STAT3 expression, STAT3 knockout (KO) or overexpression (OE), significantly affected the exosome biogenesis and also the potency of C26 conditioned medium (CM) in inducing muscle atrophy and lipolysis in vitro. The genetic manipulation of STAT3 expression caused change in phosphorylation of PKM2 and glycolysis. PKM2/SNAP23 pathway was involved in regulation of exosome biogenesis by STAT3 genetic manipulation as well as by STAT3 inhibitors in C26 cells. Mice inoculated with STAT3 knockout or overexpression C26 cells exhibited ameliorated or aggravated cancer cachexia symptoms, with a positive correlation with the serum exosome and IL-6 levels. The STAT3/PKM2/SNAP23 pathway was affected in C26 tumor tissues with genetic manipulation of STAT3 expression. The capacity of exosome biogenesis of different human cancer cells also exhibited a positive correlation with the activation of STAT3/PKM2/SNAP23 pathway. The research presented here confirms that STAT3 plays a critical role in regulating biogenesis of tumor-derived exosomes which could contribute to cancer cachexia development.
Lung cancer (LC) incidence and mortality continue to increase annually worldwide. LC is insidious and readily metastasizes and relapses. Except for its early diagnosis and surgical resection, there is no effective cure for advanced metastatic LC, and the prognosis remains dismal. Exosomes, a class of nano-sized extracellular vesicles produced by healthy or diseased cells, are coated with a bilayer lipid membrane and contain various functional molecules such as proteins, lipids, and nucleic acids. They can be used for intracellular or intercellular signaling or the transportation of biological substances. A growing body of evidence supports that exosomes play multiple crucial roles in the occurrence and metastatic progression of many malignancies, including LC. The elucidation of the potential roles of exosomes in the initiation, invasion, and metastasis of LC and their underlying molecular mechanisms may contribute to improved early diagnosis and treatment.
