Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang M
PROVIDER: S-EPMC8636640 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND: Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer. METHODS: Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan's blue lymphangiography. Tumoral lymphatics were delineated with both Evan's blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing. RESULTS: Mice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls. CONCLUSIONS: Our data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.
| S-EPMC3929486 | biostudies-literature
Project description:AIM:To determine the rate of abdominal lymph node metastasis after radical surgery for esophageal cancer and define the radiotherapy target area. METHODS:Of the 1593 patients who underwent R0 radical esophagectomy for thoracic esophageal squamous cell carcinoma (TE-SCC), 148 developed abdominal lymph node (LN) metastases within three years of surgery. During that time interval, patients were examined by various imaging methods (enhanced computer tomography, magnetic resonance imaging, and positron emission tomography-CT) at set time points. The emerging recurrence pattern, preferred sites for abdominal metastasis, and correlation with added clinical factors were carefully recorded, to permit for delineation of a target area for radiotherapy. RESULTS:We found postoperative metastatic abdominal LNs in 9.3% of the patients treated for esophageal cancer. Lesions in the upper, middle, and lower esophageal segments metastasized to abdominal LNs at 2.3%, 7.8%, and 26.6% (P < 0.0001), respectively. Of all cases, 4.8% had fewer than two affected LNs, while 20.1% had more than three metastatic LNs (P< 0.0001). The metastasis rates of negative and positive celiac LNs were 4.6% and 22.7%, respectively. Abdominal LN metastasis rates for the following LNs: 16a2 and 16a1 of para-aortic, celiac artery, posterior surface of the pancreatic head and common hepatic artery were 64.9%, 41.2%, 37.8%, 32.4%, and 20.9%, respectively. The overall rate of metastasis to these groups of LNs was 91.9%. CONCLUSION:This study determined that stations 16a1 and 16a2 of the para-aortic, truncus coeliacus, posterior surface of the pancreatic head, and arteria hepatica communis lymph nodes were the preferred sites for abdominal LN metastasis, thus defining target areas for postoperative radiotherapy.
| S-EPMC5634562 | biostudies-literature
Project description:Most cancers are old age-related diseases. Patients with lymphatic metastasis have an extremely poor prognosis in esophageal cancers (ECs). Previous studies showed ultraconserved RNAs are involved in tumorigenesis and ultraconserved RNA 189 (uc.189) served as an oncogene in cervical cancer, but the effect of exosomal uc.189 in esophageal squamous cell carcinoma (ESCC) remains undefined. This study revealed that uc.189 is closely correlated with lymph node (LN) metastasis and the number of lymphatic vessels in ESCC. ESCC-secreted exosomal uc.189 is transferred into human lymphatic endothelial cells (HLECs) to promote its proliferation, migration and tube formation to facilitate lymph node metastasis. Mechanistically, uc.189 regulated EPHA2 expression by directly binding to its 3'UTR region through dual-luciferase reporter assay. Over-expression and knockdown of EPHA2 could respectively rescue and simulate the effects induced by exosomal uc.189. Especially, the uc.189-EPHA2 axis activates the P38MAPK/VEGF-C pathway in HLECs. Finally, ESCC-secreted exosomal of uc.189 promotes HLECs sprouting in vitro, migration, and lymphangiogenesis. Thus, these findings suggested that exosomal uc.189 targets the EPHA2 of HLECs to promote lymphangiogenesis, and may represent a novel marker of diagnosis and treatment for ESCC patients in early stages.
| S-EPMC8202844 | biostudies-literature
Project description:Tumor-associated lymphatics are postulated to provide a transit route for disseminating metastatic cells. This notion is supported by preclinical findings that inhibition of pro-lymphangiogenic signaling during tumor development reduces cell spread to sentinel lymph nodes (SLNs). However, it is unclear how lymphatics downstream of SLNs contribute to metastatic spread into distal organs, or if modulating distal lymph transport impacts disease progression. Utilizing murine models of metastasis, longitudinal in vivo imaging of lymph transport, and function blocking antibodies against two VEGF family members, we provide evidence that distal lymphatics undergo disease course-dependent up-regulation of lymph transport coincidental with structural remodeling. Inhibition of VEGF-C activity with antibodies against VEGF-C or NRP2 prevented these disease-associated changes. Furthermore, utilizing a novel model of adjuvant treatment, we demonstrate that antagonism of VEGF-C or NRP2 decreases post SLN metastasis. These data support a potential therapeutic strategy for inhibiting distant metastatic dissemination via targeting tumor-associated lymphatic remodeling.
| S-EPMC3712991 | biostudies-literature
Project description:Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.
| S-EPMC6925245 | biostudies-literature
Project description:Post-transcriptional control of mRNA by micro-RNAs (miRNAs) represents an important mechanism of gene regulation. miRNAs act by binding to the 3' untranslated region (3'UTR) of an mRNA, affecting the stability and translation of the target mRNA. Here, we present a numerical model of miRNA-mediated mRNA downregulation and its application to analysis of temporal microarray data of HepG2 cells transfected with miRNA-124a. Using the model our analysis revealed a novel mechanism of mRNA accumulation control by miRNA, predicting that specific mRNAs are controlled in a digital, switch-like manner. Specifically, the contribution of miRNAs to mRNA degradation is switched from maximum to zero in a very short period of time. Such behaviour suggests a model of control in which mRNA is at a certain moment protected from binding of miRNA and further accumulates with a basal rate. Genes associated with this process were identified and parameters of the model for all miRNA-124a affected mRNAs were computed.
| S-EPMC2919720 | biostudies-literature
Project description:Lymphatic vessels are the major routes of human esophageal squamous cell carcinoma (ESCC) metastasis. Tumor cells secrete pro-lymphangiogenic factors to induce new lymphatic vessels, promoting lymph node metastasis. In this study, we show that RAS association domain family 8 (RASSF8) expression in ESCC clinical samples was inversely correlated with lymph node metastasis and patients survival. Tumor cells with low RASSF8 expression had higher apparent migratory ability, and promoted and lymphangiogenesis both in vitro and in vivo. RASSF8 downregulation enhanced VEGF-C expression and caused subcellular redistribution of p65 in ESCC. Our results show that RASSF8 acts as a tumor suppressor in ESCC and is a potential therapeutic target for preventing lymph node metastasis.
| S-EPMC4741469 | biostudies-literature
Project description:Circular RNAs (circRNAs) are a type of endogenous non-coding RNA with multiple binding sites that specifically bind to microRNAs (miRNAs) and serve an important role in cellular regulatory networks. Patients exhibit varying levels of lymphatic metastasis in a clinical setting. The present study investigated the association between circRNAs and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC). The tissue samples were divided into three groups, including early tumor stage associated with advanced nodal stage (T1 group), advanced tumor stage associated with early nodal stage (T2 group) and healthy esophageal epithelial tissues as the control group (C group). Gene chip analysis identified circRNAs, and those with possible regulatory functions were validated by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR). circRNAs containing miRNA response element (MRE) sequences were obtained, and circRNA/miRNA prediction software was used to predict miRNAs that may interact with circRNA. A total of 12,275 circRNAs were detected, including 861 with statistically significant differences. A comparison between the T1 and C groups identified 152 upregulated circRNAs and 431 downregulated ones, while a comparison between the T2 and C groups identified 187 upregulated and 481 downregulated circRNAs. A T1/T2 group comparison revealed that four circRNAs were upregulated and seven were downregulated (fold change >1.5; P<0.05). The RT-qPCR data and gene chip analysis consistently identified hsa_circRNA_100873 as differentially expressed among the examined groups. A total of five potential MREs and complementary sequences were selected for hsa_circRNA_100873. The results of the present study indicated that multiple differentially expressed circRNAs are involved in the pathogenesis of ESCC, and that upregulation of hsa_circRNA_100873 may be associated with increased lymphatic metastases in ESCC.
| S-EPMC6865678 | biostudies-literature
Project description:Cancer-cell-released exosomal microRNAs (miRNAs) are important mediators of cell-cell communication in the tumor microenvironment. In this study, we sequenced serum exosome miRNAs from esophageal squamous cell carcinoma (ESCC) patients and identified high expression of miR-320b to be closely associated with peritumoral lymphangiogenesis and lymph node (LN) metastasis. Functionally, miR-320b could be enriched and transferred by ESCC-released exosomes directly to human lymphatic endothelial cells (HLECs), promoting tube formation and migration in vitro and facilitating lymphangiogenesis and LN metastasis in vivo as assessed by gain- and loss-of-function experiments. Furthermore, we found programmed cell death 4 (PDCD4) as a direct target of miR-320b through bioinformatic prediction and luciferase reporter assay. Re-expression of PDCD4 could rescue the effects induced by exosomal miR-320b. Notably, the miR-320b-PDCD4 axis activates the AKT pathway in HLECs independent of vascular endothelial growth factor-C (VEGF-C). Moreover, overexpression of miR-320b promotes the proliferation, migration, invasion, and epithelial-mesenchymal transition progression of ESCC cells. Finally, we demonstrate that METTL3 could interact with DGCR8 protein and positively modulate pri-miR-320b maturation process in an N6-methyladenosine (m6A)-dependent manner. Therefore, our findings uncover a VEGF-C-independent mechanism of exosomal and intracellular miR-320b-mediated LN metastasis and identify miR-320b as a novel predictive marker and therapeutic target for LN metastasis in ESCC. Graphical abstract Liu et al. indicated that high levels of serum exosomal miR-320b are associated with LN metastasis and uncovered a VEGF-C-independent mechanism of exosomal and intracellular miR-320b-mediated LN metastasis in ESCC, which identify miR-320b as a novel predictive marker and therapeutic target for LN metastasis in ESCC.
| S-EPMC8526502 | biostudies-literature
Project description:To establish treatments to improve the prognosis of cancer patients, it is necessary to find new targets to control metastasis. We found that expression of FilaminC (FLNC), a member of the actin binding and cross-linking filamin protein family is correlated with lymphatic invasion and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) by increasing cell motility through activation of Rho GTPase.Immunohistochemistry analysis showed that FLNC expression in ESCC is associated with lymphatic invasion, metastasis, and prognosis. FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays. Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42). Our results suggest that FLNC expression is a useful biomarker of ESCC metastatic tendency and that inhibiting FLNC function may be useful to control the metastasis of ESCC.
| S-EPMC5351637 | biostudies-literature