Gene Summary

Gene:TUBE1; tubulin epsilon 1
Aliases: TUBE, dJ142L7.2
Summary:This gene encodes a member of the tubulin superfamily. This protein localizes to the centriolar sub-distal appendages that are associated with the older of the two centrioles after centrosome duplication. This protein plays a central role in organization of the microtubules during centriole duplication. A pseudogene of this gene is found on chromosome 5.[provided by RefSeq, Jan 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tubulin epsilon chain
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TUBE1 (cancer-related)

Jung YY, Woo HY, Kim HS
Targeted Genomic Sequencing Reveals Novel
Anticancer Res. 2019; 39(6):2883-2889 [PubMed] Related Publications
BACKGROUND/AIM: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS).
MATERIALS AND METHODS: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated.
RESULTS: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity.
CONCLUSION: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.

Zang W, Bian H, Huang X, et al.
Traditional Chinese Medicine (TCM)
Anticancer Res. 2019; 39(6):2739-2747 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).
MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.
RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.
CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

Zhao S, Li J, Zhang G, et al.
Exosomal miR-451a Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Targeting LPIN1.
Cell Physiol Biochem. 2019; 53(1):19-35 [PubMed] Related Publications
BACKGROUND/AIMS: Emerging evidence suggests that exosomal microRNAs (miRNAs) mediate hepatoma progression through the post-translational regulation of their targets. However, characteristically-expressed miRNAs and their functions in the tumor and tumor-associated angiogenesis remain poorly understood.
METHODS: miRNA sequencing (HiSeq 2500 SE50) was performed to identify miRNA species that are involved in the hepatocellular carcinoma (HCC) pathogenesis. We identified miR-451a downregulation according to its expression and TCGA analysis. miR-451a was found to be mainly involved in cell viability, apoptosis, cell cycle and migration both in HCC and endothelial cell lines. LPIN1 was predicted to be a target of this miRNA based on TargetScan, GSEA analysis, and the Uniprot database. We performed real time PCR and dual luciferase assays to confirm these results.
RESULTS: We identified that miR-451a is significantly downregulated in serum-derived exosomes from HCC patients, as compared to expression in those from normal individuals. We further confirmed that overexpression of miR-451a functions in HCC and endothelia cells in vitro and in vivo. Exosomal miR-451a, as a tumor suppressor, was found to induce apoptosis both in HCC cell lines and human umbilical vein endothelial cells (HUVECs). In addition, miR-451a suppressed HUVEC migration, tube formation, and vascular permeability. Importantly, we demonstrated that LPIN1 is a critical target of miR-451a, and promotes apoptosis in both HCC and endothelial cells.
CONCLUSION: Our study provides the novel finding that exosomal miR-451a targets LPIN1 to inhibit hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis. These results have clinical implications regarding the deregulation of miRNAs in HCC.

Stasenko M, Cybulska P, Feit N, et al.
Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status.
Gynecol Oncol. 2019; 154(1):144-149 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVE: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM).
METHODS: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used.
RESULTS: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis.
CONCLUSION: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.

Yang MH, Chang KJ, Li B, Chen WS
Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer.
Biomed Res Int. 2019; 2019:4647252 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As

Zhang Q, Lu S, Li T, et al.
ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway.
J Exp Clin Cancer Res. 2019; 38(1):173 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.
METHODS: The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.
RESULTS: ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.
CONCLUSIONS: Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.
TRIAL REGISTRATION: Retrospectively registered.

Wang T, Xing Y, Meng Q, et al.
Mammalian Eps15 homology domain 1 potentiates angiogenesis of non-small cell lung cancer by regulating β2AR signaling.
J Exp Clin Cancer Res. 2019; 38(1):174 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Non-small cell lung cancer (NSCLC) is a devastating disease with a heterogeneous prognosis, and the molecular mechanisms underlying tumor progression remain elusive. Mammalian Eps15 homology domain 1 (EHD1) plays a promotive role in tumor progression, but its role in cancer angiogenesis remains unknown. This study thus explored the role of EHD1 in angiogenesis in NSCLC.
METHODS: The changes in angiogenesis were evaluated through human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation assays. The impact of EHD1 on β2-adrenoceptor (β2AR) signaling was evaluated by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and enzyme-linked immunosorbent assay (ELISA). The interaction between EHD1 and β2AR was confirmed by immunofluorescence (IF) and coimmunoprecipitation (Co-IP) experiments, and confocal microscopy immunofluorescence studies revealed that β2AR colocalized with the recycling endosome marker Rab11, which indicated β2AR endocytosis. Xenograft tumor models were used to investigate the role of EHD1 in NSCLC tumor growth.
RESULTS: The microarray analysis revealed that EHD1 was significantly correlated with tumor angiogenesis, and loss- and gain-of-function experiments demonstrated that EHD1 potentiates HUVEC proliferation, migration and tube formation. EHD1 knockdown inhibited β2AR signaling activity, and EHD1 upregulation promoted vascular endothelial growth factor A (VEGFA) and β2AR expression. Interestingly, EHD1 interacted with β2AR and played a novel and critical role in β2AR endocytic recycling to prevent receptor degradation. Aberrant VEGFA or β2AR expression significantly affected EHD1-mediated tumor angiogenesis. The proangiogenic role of EHD1 was confirmed in xenograft tumor models, and immunohistochemistry (IHC) analysis confirmed that EHD1 expression was positively correlated with VEGFA expression, microvessel density (MVD) and β2AR expression in patient specimens.
CONCLUSION: Collectively, the data obtained in this study suggest that EHD1 plays a critical role in NSCLC angiogenesis via β2AR signaling and highlight a potential target for antiangiogenic therapy.

Imafuji H, Matsuo Y, Ueda G, et al.
Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL‑8 production in pancreatic cancer.
Oncol Rep. 2019; 41(6):3508-3516 [PubMed] Related Publications
Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem‑R). To elucidate the mechanism of Gem‑R, two Gem‑R PaCa cell lines were established from AsPC‑1 and MIA PaCa‑2 cells. It was demonstrated that expression of interleukin‑8 (IL‑8) mRNA was significantly upregulated in Gem‑R PaCa cells by cDNA microarray and RT‑qPCR analyses. Increased IL‑8 secretion by Gem‑R cells was confirmed by cytokine array and enzyme‑linked immunosorbent assay. Moreover, we found that co‑culture with Gem‑R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti‑CXCR2 (main receptor for IL‑8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL‑8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem‑R increased IL‑8 production and consequently increased tumor angiogenesis, the IL‑8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem‑R.

Tang E, Wang Y, Liu T, Yan B
Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer.
Gene. 2019; 704:42-48 [PubMed] Related Publications
Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced β-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/β-catenin/VEGF axis in GC.

Hu C, Cheng X, MingYu Q, et al.
The effects of microRNA-1224-5p on hepatocellular carcinoma tumor endothelial cells.
J Cancer Res Ther. 2019; 15(2):329-335 [PubMed] Related Publications
Aim: The aim of this study was to investigate the effect of microRNA-1224-5p (miR-1224-5p) on tumor endothelial cells (TECs) of human hepatocellular carcinoma (HCC).
Subjects and Methods: Oligonucleotides were chemically synthesized and transfected into TECs using Lipofectamine 2000. TECs were divided into three groups, namely a control (CON) group without transfection, a negative control (NC) group transfected with negative control oligonucleotides and green fluorescent protein (GFP), and a micro-up (MU) group transfected with miR-1224-5p mimic and GFP. The expression of miR-1224-5p was quantified via quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The proliferation of TECs was detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the optical density value at 490 nm was measured after every 24 h. Apoptosis was detected via flow cytometry using a 7-aminoactinomycin/APC Annexin V kit. The migration and invasion of TECs were detected using transwell assay. The tube formation ability was evaluated using the tube formation assay.
Results: Oligonucleotides were successfully transduced into TECs, and the expression of miR-1224-5p was specifically upregulated. The results of qRT-PCR analysis showed that the expression of miR-1224-5p was significantly upregulated in the MU group (2
Conclusions: miR-1224-5p may serve as a potential tumor suppressor in HCC. Upregulation in miR-1224-5p expression may decrease proliferation, induce apoptosis, inhibit migration and invasion, and suppress tube formation in TECs of human HCC.

Shi Y, Song Y, Liu P, Li P
YKL-40 can promote angiogenesis in sporadic cerebral cavernous malformation (CCM).
J Clin Neurosci. 2019; 64:220-226 [PubMed] Related Publications
The factors affecting the formation of sporadic CCMs remain unclear. A cDNA microarray was used to identify characteristic gene expression patterns in sporadic CCMs. Transcription level of YKL-40 was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). The location and expression were revealed by immunochemistry, immunofluorescence staining and level of YKL-40 was quantified by Western blotting. Alterations to endothelial function following the up or down regulation of gene expression was assessed by Transwell assays, cell counting kit-8 assays and capillary-like tube formation assays in human brain microvascular endothelial cells (HBMECs) in vitro. We generated a murine model by stereotaxically injecting HBMECs with expressing amounts of YKL-40 into the brain. cDNA microarray and RT-PCR results revealed that the transcription level of YKL-40 was ≥140-fold higher in sporadic CCMs in healthy controls. Histological staining revealed excessive YKL-40 expression in the CCM endothelium. Western blotting results analysis showed that YKL-40 protein expression was significantly higher in CCM endothelium (P < 0.05). YKL-40 over-expressing HBMECs showed increased cell proliferation, migration and tube formation ability compared with the control group, whereas downregulating of YKL-40 inhibited the proliferation, migration of HBMECs and capillary-like tube formation (P < 0.05). In animals, increased of YKL-40 was associated with abnormal vascular lesions that were similar to CCMs. YKL-40 is over-expressed in the CCM endothelium and acts as an angiogenic factor that promotes the pathogenesis of sporadic CCMs. YKL-40 may therefore represent a potential therapeutic target in the treatment of sporadic CCM.

Wang HF, Wang SS, Zheng M, et al.
Hypoxia promotes vasculogenic mimicry formation by vascular endothelial growth factor A mediating epithelial-mesenchymal transition in salivary adenoid cystic carcinoma.
Cell Prolif. 2019; 52(3):e12600 [PubMed] Related Publications
OBJECTIVES: To investigate the role of hypoxia in vasculogenic mimicry (VM) of salivary adenoid cystic carcinoma (SACC) and the underlying mechanism involved.
MATERIALS AND METHODS: Firstly, wound healing, transwell invasion, immunofluorescence and tube formation assays were performed to measure the effect of hypoxia on migration, invasion, EMT and VM of SACC cells, respectively. Then, immunofluorescence and RT-PCR were used to detect the effect of hypoxia on VE-cadherin and VEGFA expression. And pro-vasculogenic mimicry effect of VEGFA was investigated by confocal laser scanning microscopy and Western blot. Moreover, the levels of E-cadherin, N-cadherin, Vimentin, CD44 and ALDH1 were determined by Western blot and immunofluorescence in SACC cells treated by exogenous VEGFA or bevacizumab. Finally, CD31/ PAS staining was performed to observe VM and immunohistochemistry was used to determine the levels of VEGFA and HIF-1α in 95 SACC patients. The relationships between VM and clinicopathological variables, VEGFA or HIF-1α level were analysed.
RESULTS: Hypoxia promoted cell migration, invasion, EMT and VM formation, and enhanced VE-cadherin and VEGFA expression in SACC cells. Further, exogenous VEGFA markedly increased the levels of N-cadherin, Vimentin, CD44 and ALDH1, and inhibited the expression of E-cadherin, while the VEGFA inhibitor reversed these changes. In addition, VM channels existed in 25 of 95 SACC samples, and there was a strong positive correlation between VM and clinic stage, distant metastases, VEGFA and HIF-1α expression.
CONCLUSIONS: VEGFA played an important role in hypoxia-induced VM through regulating EMT and stemness, which may eventually fuel the migration and invasion of SACC.

Blok F, Dasgupta S, Dinjens WNM, et al.
Retrospective study of a 16 year cohort of BRCA1 and BRCA2 carriers presenting for RRSO: Prevalence of invasive and in-situ carcinoma, with follow-up.
Gynecol Oncol. 2019; 153(2):326-334 [PubMed] Related Publications
OBJECTIVES: Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years. Most of these carcinomas are believed to arise in the fallopian tube from serous tubal intraepithelial carcinoma (STIC). We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up.
METHODS: Consecutive BRCA1/2 carriers presenting for an RRSO at Erasmus MC (2000-2016) were studied. SEE-FIM pathology protocol was followed from 2010 onwards. For the cases with carcinoma and/or STIC, the histology was reviewed and immunohistochemistry (p53 & MIB-1) was performed. Next Generation Targeted Sequencing (NGTS) for TP53 mutation was used to establish clonality in 2 cases.
RESULTS: Of the 527 included patients, 68% were BRCA1, 31.6% were BRCA2, and 0.4% carried both mutations. The prevalence of high grade serous carcinoma was 2.3% (12/527); 59% of these were of tubal origin. High grade serous carcinoma was more common in patients operated on after the recommended age (p = 0.03). Isolated STIC was present in 0.8% (4/527). Two BRCA1 carriers with isolated STIC at RRSO developed peritoneal serous carcinoma >7 years later. Identical TP53 mutations in the peritoneal serous carcinoma and the preceding STIC established their clonal origin.
CONCLUSIONS: High grade serous carcinoma is more common in BRCA1/2 carriers presenting for RRSO after the recommended age, and is more often of tubal origin. Longer follow up of patients with STIC at RRSO should be considered.

Fang Y, Sun B, Wang J, Wang Y
miR-622 inhibits angiogenesis by suppressing the CXCR4-VEGFA axis in colorectal cancer.
Gene. 2019; 699:37-42 [PubMed] Related Publications
Angiogenesis is essential for tumor metastasis. Our previous study has revealed that miR-622 inhibits colorectal cancer (CRC) metastasis. Here, we aimed to explore the effects and potential molecular mechanisms of action of miR-622 on angiogenesis. We found that overexpression of miR-622 inhibited CRC angiogenesis in vitro, according to suppression of proliferation, migration, tube formation, and invasiveness of human umbilical vein endothelial cells (HUVECs) treated with a tumor cell-conditioned medium derived from Caco-2 or HT-29 cells. Likewise, enhanced miR-622 expression suppressed CRC angiogenesis in vivo as determined by the measurement of Ki67 and VEGFA levels and microvessel density (by immunostaining). CXCR4, encoding a positive regulator of vascular endothelial growth factor A (VEGFA), was shown to be a direct target of miR-622. Overexpression of CXCR4 attenuated the inhibition of VEGFA expression by miR-622 and reversed the loss of tumor angiogenesis caused by miR-622. Taken together, these data show that miR-622 inhibits CRC angiogenesis by suppressing the CXCR4-VEGFA signaling axis, which represents a promising target for developing a new therapeutic strategy against CRC.

Mori H, Tomiyasu T, Nishiyama K, et al.
L233P mutation in the bovine leukemia virus Tax protein depresses endothelial cell recruitment and tumorigenesis in athymic nude mice.
Arch Virol. 2019; 164(5):1343-1351 [PubMed] Related Publications
Bovine leukemia virus (BLV) can be divided into two categories based on the amino acid at position 233 in the Tax protein, which probably plays a crucial role in leukemogenesis. We show here that a rat fibroblast cell line stably expressing L233-Tax formed significantly larger tumors than P233-Tax-expressing cells in a murine xenograft study. Although the microvessel density was comparable in both tumors, visible blood vessel invasion was observed only on tumors from L233-Tax-expressing cells. Endothelial cell tube formation assays using human umbilical vein endothelial cells showed no significant difference in angiogenic activity between conditioned medium from L233- and P233-Tax-expressing cells, whereas in vitro chemotaxis assays revealed that only L233-Tax-expressing cells produced a chemoattractant for endothelial cells. Since pathological neovascularization can occur from the recruitment of endothelial progenitor cells, these results suggest that L233-Tax-expressing cells recruit murine endothelial progenitor cells and promote neovascularization to support tumor growth. BLV-infected lymphoma cells may also recruit bovine endothelial progenitor cells to promote neovascularization. The findings of this study are consistent with our previous observation that BLV carrying P233-Tax has a significantly longer incubation period for developing tumors than the virus carrying L233-Tax and provide insight into the function of Tax in leukemogenesis by BLV.

Xu W, Qian J, Zeng F, et al.
Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment.
J Exp Clin Cancer Res. 2019; 38(1):114 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood.
METHODS: The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models.
RESULTS: PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis.
CONCLUSIONS: These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment.

Morse CB, Toukatly MN, Kilgore MR, et al.
Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma.
Gynecol Oncol. 2019; 153(2):217-222 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
OBJECTIVE: The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival.
METHODS: Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
RESULTS: Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25-0.59)).
CONCLUSIONS: Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.

Yeo C, Lee HJ, Lee EO
Serum promotes vasculogenic mimicry through the EphA2/VE-cadherin/AKT pathway in PC-3 human prostate cancer cells.
Life Sci. 2019; 221:267-273 [PubMed] Related Publications
AIMS: Serum is widely used for in vitro cell culture of eukaryotic cells. Although serum is well known to affect various biological activities in cancer cells, its effect in vasculogenic mimicry (VM) is not yet fully defined. Thus, this study investigated the role of serum in VM in human prostate cancer (PCa) PC-3 cells.
MAIN METHODS: Invasion assay and 3D culture VM tube formation assay are performed. VM-related molecules are checked by western blot and reverse transcriptase-polymerase chain reaction. Nuclear twist is detected by confocal after twist-FITC/DAPI double staining.
KEY FINDINGS: Serum dramatically induced not only invasion but also VM. Serum increased the phosphorylation of erythropoietin-producing hepatocellular A2 (EphA2) without affecting EphA2 expression. Both the protein and mRNA expression levels of vascular endothelial cadherin (VE-cadherin) are up-regulated by serum. Twist expression was increased in the nucleus by serum. Serum activated AKT through phosphorylation, despite the unchanged AKT expression. Serum caused an increase in matrix metalloproteinase-2 (MMP-2) and laminin subunit 5 gamma-2 (LAMC2) protein expressions. Wortmannin, a phosphoinositide-3-kinase inhibitor, significantly decreased serum-induced invasion and VM.
SIGNIFICANCE: These results demonstrated that serum activates EphA2 and up-regulates twist/VE-cadherin, which in turn activate AKT that up-regulates MMP-2 and LAMC2, thereby inducing the invasion and VM of human PCa PC-3 cells.

Huang YW, Tsai HC, Wang SW, et al.
Amphiregulin Promotes Vascular Endothelial Growth Factor-C Expression and Lymphangiogenesis through STAT3 Activation in Human Chondrosarcoma Cells.
Cell Physiol Biochem. 2019; 52(1):1-15 [PubMed] Related Publications
BACKGROUND/AIMS: Chondrosarcoma is the second most common primary malignancy of bone, characterized by a high metastatic potential. Increasing clinical data highlight the important role played by lymphangiogenesis in cancer metastasis. Amphiregulin (AR) has been implicated in tumor metastasis and lymphangiogenesis, but its association with vascular endothelial growth factor-C (VEGF-C) expression and lymphangiogenesis in chondrosarcoma is unclear.
METHODS: We used qPCR, ELISA and Western blotting to detect AR-induced VEGF-C expression in chondrosarcoma cells. Lymphangiogenesis was investigated by lymphatic endothelial cells (LECs) migration and tube formation. An in vivo experiment examined AR expression in tumor-associated lymphangiogenesis.
RESULTS: In this study, we found that both AR and VEGF-C expression correlated with tumor stage and were significantly higher than levels found in normal cartilage. Exogenous AR promoted VEGF-C expression in chondrosarcoma cells in a time- and dose-dependent manner and subsequently increased migration and tube formation of LECs. AR also increased VEGF-C expression and lymphangiogenesis through the Src/MEK/ERK/STAT3 signaling pathway. However, it is unclear as to how an EGFR ligand (AR) induces activation of the Src kinase. Knockdown of AR decreased VEGF-C expression in chondrosarcoma cells. Similarly, lymphangiogenesis was abolished in AR knockdown cells in an in vivo model of chondrosarcoma.
CONCLUSION: These results indicate that AR occurs through the Src/MEK/ERK/STAT-3 pathway, activating VEGF-C expression and contributing to lymphangiogenesis in human chondrosarcoma. Thus, AR could be a therapeutic target in metastasis and lymphangiogenesis of chondrosarcoma.

Wu S, Ou T, Xing N, et al.
Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer.
Nat Commun. 2019; 10(1):720 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conduct whole-genome and targeted sequencing in urothelial bladder carcinomas (UBCs, the most common type of bladder cancer). Recurrent mutations in noncoding regions affecting gene regulatory elements and structural variations (SVs) leading to gene disruptions are prevalent. Notably, we find recurrent ADGRG6 enhancer mutations and FRS2 duplications which are associated with higher protein expression in the tumor and poor prognosis. Functional assays demonstrate that depletion of ADGRG6 or FRS2 expression in UBC cells compromise their abilities to recruit endothelial cells and induce tube formation. Moreover, pathway assessment reveals recurrent alterations in multiple angiogenesis-related genes. These results illustrate a multidimensional genomic landscape that highlights noncoding mutations and SVs in UBC tumorigenesis, and suggest ADGRG6 and FRS2 as novel pathological angiogenesis regulators that would facilitate vascular-targeted therapies for UBC.

Suda K, Nakaoka H, Hata C, et al.
Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report.
Diagn Pathol. 2019; 14(1):17 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Retroperitoneal high-grade serous carcinoma (HGSC) is extremely rare and the origin remains unclear. We present a case of retroperitoneal HGSC and coexisting serous tubal intraepithelial carcinoma (STIC), which is considered as the main origin of ovarian HGSC. We reviewed the available literature and discussed about the origin of this rare disease.
CASE PRESENTATION: A 58-year-old female with a 93 × 65 × 62 mm-solid tumor with a cystic part was located immediately dorsal to the rectum underwent bilateral salpingo-oophorectomy, total abdominal hysterectomy, and en bloc resection of the retroperitoneal tumor together with lower anterior resection of the rectum. Histological diagnosis was retroperitoneal HGSC and STIC at the right fallopian tube. Two deleterious somatic mutations in TP53 and BRCA2 genes were shared between retroperitoneal HGSC and STIC.
CONCLUSIONS: In addition to clinical features in the previous reports, our genetic findings suggest the origin of retroperitoneal HGSC might be STIC.

He Z, Ruan X, Liu X, et al.
FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.
J Exp Clin Cancer Res. 2019; 38(1):65 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.
METHODS: The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .
RESULTS: We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.
CONCLUSION: Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Xu MR, Wei PF, Suo MZ, et al.
Brucine Suppresses Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cell Line MDA-MB-231.
Biomed Res Int. 2019; 2019:6543230 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

Yang M, Liu J, Wang F, et al.
Lysyl oxidase assists tumor‑initiating cells to enhance angiogenesis in hepatocellular carcinoma.
Int J Oncol. 2019; 54(4):1398-1408 [PubMed] Related Publications
A highly tumorigenic and malignant sub‑population of HCC containing tumor‑initiating cells (TICs) are defined by high self‑renewal and sphere formation ability. Lysyl oxidase (LOX) regulates various factors involved in extracellular matrix (ECM) maintenance, migration and angiogenesis. Certain reports have demonstrated the role of LOX in ECM crosslinking, however, the cancer‑promoting effects of LOX in HCC remain unclear, and whether LOX has a role in the regulation of angiogenesis in HCC TICs has not been elucidated. In the current study, RNA sequencing using next‑generation sequencing technology and bioinformatics analyses revealed that LOX gene expression was significantly upregulated in cell spheres. Sphere cells may form tumors with more vascular enrichment compared with tumors produced from adherent cells, as observed in a mouse xenograft model. LOX expression is correlated with increased vascular endothelial growth factor (VEGF) and platelet‑derived growth factor, as demonstrated by analyses of The Cancer Genome Atlas and Gene Expression Omnibus databases. Conditioned media obtained from LOX‑overexpressing tumor cells stimulated angiogenesis via secreted VEGF and enhanced the tube formation capacity of endothelial cells. Furthermore, these functional behaviors were blocked by the LOX inhibitor β‑aminopropionitrile. These findings provide novel mechanistic insight into the pivotal role of LOX in the regulation of TICs in HCC. Combination of LOX inhibitor with sorafenib is a potentially advantageous strategy for HCC therapy.

Li W, Fu Q, Man W, et al.
LncRNA OR3A4 participates in the angiogenesis of hepatocellular carcinoma through modulating AGGF1/akt/mTOR pathway.
Eur J Pharmacol. 2019; 849:106-114 [PubMed] Related Publications
Hepatocellular carcinoma (HCC), as the commonest type in liver cancer, is in urgent need for better treatment target due to its high mortality and poor prognosis. The involvement of angiogenesis in HCC has been identified by multiple studies, but the underlying mechanism remains unclear. Long non-coding RNAs (LncRNAs) have been reported to regulate numerous cancers, including HCC. LncRNA-OR3A4 has been reported to exert oncogenic and angiogenetic functions in gastric cancer, but its role in HCC hasn't been elucidated. Present study aimed to uncover the biological role of OR3A4 in tumor progression and angiogenesis in HCC. The upregulation of OR3A4 in HCC tissues and cell lines and its prognostic significance were first identified. Loss-of-function assays, including CCK-8, transwell and tube formation assay, validated OR3A4 as a promoter for HCC progression and angiogenesis. The association of OR3A4 and AGGF1 with HCC and poor prognosis was identified by qRT-PCR and Kaplan-Meier analysis. Western blotting and spearman's correlation curve verified the effect of OR3A4 on AGGF1 level and their positive association. Rescue assays revealed that OR3A4 promoted cancer progression and angiogenesis in HCC via AGGF1/akt/mTOR. Together, present study revealed OR3A4 as a novel prognostic target for HCC, which regulated tumor progression and angiogenesis through AGGF1/akt/mTOR pathway.

Sun Y, Wang W, Guo Y, et al.
High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: Population-based and in vitro studies.
Toxicol Appl Pharmacol. 2019; 365:101-111 [PubMed] Related Publications
Although the adverse effects of copper overexposure on the liver, kidney, spleen and intestinal organs are well known, information about the impact of copper toxicity on human reproduction is limited. A total of 348 infertile patients were enrolled in our present study, including 89 with polycystic ovary syndrome (PCOS), 145 with fallopian tube obstruction and 114 controls. The follicular fluid concentrations of 22 trace elements were measured by inductively coupled plasma mass spectrometry (ICP-MS). Principal component analysis was used to identify trace element profile alterations in different groups. The mRNA levels of steroidogenesis-related genes were measured by real-time PCR. Our results showed that the trace element profile in follicular fluid was obviously altered in PCOS patients. Copper concentrations were significantly (p < .05) higher in the PCOS group than in the other two groups. Increased copper levels in follicular fluid were associated with a higher number of retrievable oocytes in the PCOS group (B = 1.785, p = .001) but a lower rate of high-quality embryos (B = -6.360, p = .050). Moreover, follicular fluid copper levels were positively correlated with follicular fluid progesterone levels (r = 0.275, p = .010) and testosterone levels (r = 0.250, p = .022). Cultured human granulosa cells overexposed to copper showed significantly (p < .05) increased estradiol secretion and decreased testosterone levels. Real-time quantitative PCR revealed a significant (p < .05) increase in CYP19A1 and HSD3b mRNA expression. Our results indicate that increased copper levels in follicular fluid could affect follicle development in PCOS patients, and the mechanism may be related to copper-induced abnormalities in steroidogenesis.

Fabbro M, Moore KN, Dørum A, et al.
Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial.
Gynecol Oncol. 2019; 152(3):560-567 [PubMed] Related Publications
OBJECTIVE: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial.
METHODS: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors.
RESULTS: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%).
CONCLUSIONS: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

He Q, Zhao L, Liu X, et al.
MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change.
J Exp Clin Cancer Res. 2019; 38(1):9 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: RNA binding proteins (RBPs) have been reported to interact with RNAs to regulate gene expression. Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which involved in the angiogenesis of tumor. The purpose of this study is to elucidate the potential roles and molecular mechanisms of MOV10 and circ-DICER1 in regulating the angiogenesis of glioma-exposed endothelial cells (GECs).
METHODS: The expressions of circ-DICER1, miR-103a-3p and miR-382-5p were detected by real-time PCR. The expressions of MOV10, ZIC4, Hsp90 and PI3K/Akt were detected by real-time PCR or western blot. The binding ability of circ-SHKBP1 and miR-544a / miR-379, ZIC4 and miR-544a / miR-379 were analyzed with Dual-Luciferase Reporter System or RIP experiment. The direct effects of ZIC4 on the Hsp90β promoter were analyzed by the ChIP experiment. The cell viability, migration and tube formation in vitro were detected by CCK-8, Transwell assay and Matrigel tube formation assay. The angiogenesis in vivo was evaluated by Matrigel plug assay. Student's t-test (two tailed) was used for comparisons between two groups. One-way analysis of variance (ANOVA) was used for multi-group comparisons followed by Bonferroni post-hoc analysis.
RESULTS: The expressions of RNA binding proteins MOV10, circ-DICER1, ZIC4, and Hsp90β were up-regulated in GECs, while miR103a-3p/miR-382-5p were down-regulated. MOV10 binding circ-DICER1 regulated the cell viability, migration, and tube formation of GECs. And the effects of both MOV10 and circ-DICER1 silencing were better than the effects of MOV10 or circ-DICER1 alone silencing. In addition, circ-DICER1 acts as a molecular sponge to adsorb miR-103a-3p / miR-382-5p and impair the negative regulation of miR-103a-3p / miR-382-5p on ZIC4 in GECs. Furthermore, ZIC4 up-regulates the expression of its downstream target Hsp90β, and Hsp90 promotes the cell viability, migration, and tube formation of GECs by activating PI3K/Akt signaling pathway.
CONCLUSIONS: MOV10 / circ-DICER1 / miR-103a-3p (miR-382-5p) / ZIC4 pathway plays a vital role in regulating the angiogenesis of glioma. Our findings not only provides novel mechanisms for the angiogenesis of glioma, but also provide potential targets for anti-angiogenesis therapies of glioma.

Shi Y, Huang X, Chen G, et al.
miR-632 promotes gastric cancer progression by accelerating angiogenesis in a TFF1-dependent manner.
BMC Cancer. 2019; 19(1):14 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Gastric cancer (GC) is a common malignant disease worldwide. Aberrant miRNAs expression contributes to malignant cells behaviour, and in preclinical research, miRNA targeting has shown potential for improving GC therapy. Our present study demonstrated that miR-632 promotes GC progression in a trefoil factor 1 (TFF1)-dependent manner.
METHODS: We collected GC tissues and serum samples to detect miR-632 expression using real-time PCR. A dual-luciferase reporter assay was used to identify whether miR-632 directly regulates TFF1 expression. Tube formation and endothelial cell recruitment assays were performed with or without miR-632 treatment. Western blot and in situ hybridization assays were performed to detect angiogenesis and endothelial recruitment markers that are affected by miR-632.
RESULTS: Our results showed that miR-632 is highly expressed in GC tissue and serum and negatively associated with TFF1 in GC. miR-632 improves tube formation and endothelial cell recruitment by negatively regulating TFF1 in GC cells. Recombinant TFF1 reversed miR-632-mediated angiogenesis. TFF1 is a target gene of miR-632.
CONCLUSIONS: Our study demonstrated that miR-632 promotes GC progression by accelerating angiogenesis in a TFF1-dependent manner. Targeting of miR-632 may be a potential therapeutic approach for GC patients.

Wang Y, Song X, Zheng Y, et al.
Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment.
Int J Med Sci. 2018; 15(14):1702-1712 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.

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