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• W3025004947 abstract "Accumulating evidence shows that long noncoding RNA (lncRNA) dysregulation plays a critical role in tumor angiogenesis. Glioma is characterized by abundant angiogenesis. Herein, we investigated the expression and function of LINC00346 in the regulation of glioma angiogenesis. The present study first demonstrated that ANKHD1 (ankyrin repeat and KH domain-containing protein 1) and LINC00346 were significantly increased in glioma-associated endothelial cells (GECs), whereas ZNF655 (zinc finger protein 655) was decreased in GECs. Meanwhile, ANKHD1 inhibition, LINC00346 inhibition, or ZNF655 overexpression impeded angiogenesis of GECs. Moreover, ANKHD1 targeted LINC00346 and enhanced the stability of LINC00346. In addition, LINC00346 bound to ZNF655 mRNA through their Alu elements so that LINC00346 facilitated the degradation of ZNF655 mRNA via a STAU1 (Staufen1)-mediated mRNA decay (SMD) mechanism. Futhermore, ZNF655 targeted the promoter region of ANKHD1 and formed an ANKHD1/LINC00346/ZNF655 feedback loop that regulated glioma angiogenesis. Finally, knockdown of ANKHD1 and LINC00346, combined with overexpression of ZNF655, resulted in a significant decrease in new vessels and hemoglobin content in vivo. The results identified an ANKHD1/LINC00346/ZNF655 feedback loop in the regulation of glioma angiogenesis that may provide new targets and strategies for targeted therapy against glioma. Accumulating evidence shows that long noncoding RNA (lncRNA) dysregulation plays a critical role in tumor angiogenesis. Glioma is characterized by abundant angiogenesis. Herein, we investigated the expression and function of LINC00346 in the regulation of glioma angiogenesis. The present study first demonstrated that ANKHD1 (ankyrin repeat and KH domain-containing protein 1) and LINC00346 were significantly increased in glioma-associated endothelial cells (GECs), whereas ZNF655 (zinc finger protein 655) was decreased in GECs. Meanwhile, ANKHD1 inhibition, LINC00346 inhibition, or ZNF655 overexpression impeded angiogenesis of GECs. Moreover, ANKHD1 targeted LINC00346 and enhanced the stability of LINC00346. In addition, LINC00346 bound to ZNF655 mRNA through their Alu elements so that LINC00346 facilitated the degradation of ZNF655 mRNA via a STAU1 (Staufen1)-mediated mRNA decay (SMD) mechanism. Futhermore, ZNF655 targeted the promoter region of ANKHD1 and formed an ANKHD1/LINC00346/ZNF655 feedback loop that regulated glioma angiogenesis. Finally, knockdown of ANKHD1 and LINC00346, combined with overexpression of ZNF655, resulted in a significant decrease in new vessels and hemoglobin content in vivo. The results identified an ANKHD1/LINC00346/ZNF655 feedback loop in the regulation of glioma angiogenesis that may provide new targets and strategies for targeted therapy against glioma. Glioma is the most common tumor of the human central nervous system, which is characterized by its high degree of malignancy, high invasiveness, and poor prognosis. The median survival time of patients with glioma is still only 12 to 18 months, despite improvements in surgery, radiotherapy, and chemotherapy.1Zepecki J.P. Snyder K.M. Moreno M.M. Fajardo E. Fiser A. Ness J. Sarkar A. Toms S.A. Tapinos N. Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor.Oncogene. 2019; 38: 1734-1750Crossref PubMed Scopus (36) Google Scholar Numerous studies have shown that the formation of new blood vessels is involved in the process of tumor growth and metabolism. Thus, angiogenesis is considered to be a marker of the development and progression of malignant tumors.2Laszlo V. Valko Z. Kovacs I. Ozsvar J. Hoda M.A. Klikovits T. Lakatos D. Czirok A. Garay T. Stiglbauer A. et al.Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo.Clin. Cancer Res. 2018; 24: 3729-3740Crossref PubMed Scopus (16) Google Scholar Glioma is a solid tumor of which the growth and metastasis are dependent on angiogenesis.3Boyd N.H. Walker K. Ayokanmbi A. Gordon E.R. Whetsel J. Smith C.M. Sanchez R.G. Lubin F.D. Chakraborty A. Tran A.N. et al.Chromodomain Helicase DNA-Binding Protein 7 Is Suppressed in the Perinecrotic/Ischemic Microenvironment and Is a Novel Regulator of Glioblastoma Angiogenesis.Stem Cells. 2019; 37: 453-462Crossref PubMed Scopus (14) Google Scholar Therefore, anti-angiogenesis therapy has become an effective method for the treatment of glioma. RNA binding proteins (RBPs) play critical roles in every step of gene expression, especially in the regulation of transcription and post-transcriptional processes.4Banerjee A. Vest K.E. Pavlath G.K. Corbett A.H. Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing.Nucleic Acids Res. 2017; 45: 10706-10725Crossref PubMed Scopus (45) Google Scholar RBPs mediate mRNA splicing, the maintenance of RNA stability, and translation through the identification of specific mRNA components.5de Silva H.C. Lin M.Z. Phillips L. Martin J.L. Baxter R.C. IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer.Cell. Mol. Life Sci. 2019; 76: 2015-2030Crossref PubMed Scopus (42) Google Scholar Recent data suggest that RBPs are involved in regulating the development and progression of multiple tumors. For example, NOVA1 acts as an oncogene in melanoma development.6Yu X. Zheng H. Chan M.T.V. Wu W.K.K. NOVA1 acts as an oncogene in melanoma via regulating FOXO3a expression.J. Cell. Mol. Med. 2018; 22: 2622-2630Crossref PubMed Scopus (22) Google Scholar Overexpression of QKI-5 significantly decreases proliferation and transformation of lung cancer cells.7Zong F.Y. Fu X. Wei W.J. Luo Y.G. Heiner M. Cao L.J. Fang Z. Fang R. Lu D. Ji H. Hui J. The RNA-binding protein QKI suppresses cancer-associated aberrant splicing.PLoS Genet. 2014; 10: e1004289Crossref PubMed Scopus (159) Google Scholar The ankyrin repeat and KH domain-containing protein 1 (ANKHD1) is an RBP and plays a role in the regulation of the cell cycle and transcription.8Machado-Neto J.A. Lazarini M. Favaro P. de Melo Campos P. Scopim-Ribeiro R. Franchi Junior G.C. Nowill A.E. Lima P.R. Costa F.F. Benichou S. et al.ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells.Biochim. Biophys. Acta. 2015; 1853: 583-593Crossref PubMed Scopus (22) Google Scholar ANKHD1 is upregulated in several tumor cells (e.g., multiple myeloma and acute leukemia) and significantly reduces patient survival.9Dhyani A. Duarte A.S. Machado-Neto J.A. Favaro P. Ortega M.M. Olalla Saad S.T. ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells.FEBS Lett. 2012; 586: 4311-4318Crossref PubMed Scopus (21) Google Scholar,10Dhyani A. Machado-Neto J.A. Favaro P. Saad S.T. ANKHD1 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth.Eur. J. Cancer. 2015; 51: 252-259Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar However, the expression of ANKHD1 in glioma-associated endothelial cells (GECs) compared with astrocyte-associated endothelial cells (AECs) and the function of ANKHD1 in the regulation of angiogenesis remain poorly defined. Long noncoding RNAs (lncRNAs) belong to the noncoding genes that consist of more than 200 nucleotides. Accumulating evidence shows that lncRNAs are singularly expressed in many malignancies and may be related to the modulation of tumor development.11Mishra S. Verma S.S. Rai V. Awasthee N. Chava S. Hui K.M. Kumar A.P. Challagundla K.B. Sethi G. Gupta S.C. Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases.Cell. Mol. Life Sci. 2019; 76: 1947-1966Crossref PubMed Scopus (147) Google Scholar For instance, Linc00176 is upregulated during the malignant progression of hepatocellular carcinoma cells.12Tran D.D.H. Kessler C. Niehus S.E. Mahnkopf M. Koch A. Tamura T. Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs.Oncogene. 2018; 37: 75-85Crossref PubMed Scopus (69) Google Scholar Brain-derived neurotrophic factor-antisense (BDNF-AS) is downregulated in prostate cancer tissues and cells and predictive of poor prognosis.13Li W. Dou Z. We S. Zhu Z. Pan D. Jia Z. Liu H. Wang X. Yu G. Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer.Biomed. Pharmacother. 2018; 102: 1105-1110Crossref PubMed Scopus (30) Google Scholar The abnormal expression lncRNA-LINC00346 was filtered out using lncRNA microarray analysis in our study. LINC00346 is highly expressed in bladder cancer and functions as an oncogene.14Ye T. Ding W. Wang N. Huang H. Pan Y. Wei A. Long noncoding RNA linc00346 promotes the malignant phenotypes of bladder cancer.Biochem. Biophys. Res. Commun. 2017; 491: 79-84Crossref PubMed Scopus (37) Google Scholar However, the expression and function of LINC00346 in GECs remain unclear. The Staufen1 (STAU1)-mediated mRNA decay (SMD) is involved in the regulation of functional mRNAs and transcription.15Cho H. Kim K.M. Han S. Choe J. Park S.G. Choi S.S. Kim Y.K. Staufen1-mediated mRNA decay functions in adipogenesis.Mol. Cell. 2012; 46: 495-506Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar STAU1 is a double-stranded RNA-binding protein that binds to the STAU1-binding site (SBS) in the 3′ untranslated region (3′ UTR) of target mRNA.16Cho H. Han S. Park O.H. Kim Y.K. SMG1 regulates adipogenesis via targeting of staufen1-mediated mRNA decay.Biochim. Biophys. Acta. 2013; 1829: 1276-1287Crossref PubMed Scopus (19) Google Scholar,17Kim M.Y. Park J. Lee J.J. Ha D.H. Kim J. Kim C.G. Hwang J. Kim C.G. Staufen1-mediated mRNA decay induces Requiem mRNA decay through binding of Staufen1 to the Requiem 3'UTR.Nucleic Acids Res. 2014; 42: 6999-7011Crossref PubMed Scopus (16) Google Scholar UPF1 is an evolutionarily conserved and ubiquitously expressed phosphoprotein. STAU1 recruits UPF1 to mediate rapid mRNA degradation by SMD.18Jolly L.A. Homan C.C. Jacob R. Barry S. Gecz J. The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth.Hum. Mol. Genet. 2013; 22: 4673-4687Crossref PubMed Scopus (77) Google Scholar Zinc finger protein 655 (ZNF655) belongs to the Krüppel-like zinc-finger gene family. ZNF655 regulates the cell-cycle progression of HeLa cells.19Houlard M. Romero-Portillo F. Germani A. Depaux A. Regnier-Ricard F. Gisselbrecht S. Varin-Blank N. Characterization of VIK-1: a new Vav-interacting Kruppel-like protein.Oncogene. 2005; 24: 28-38Crossref PubMed Scopus (13) Google Scholar In this study, mRNA microarray data indicated the differentially expressed ZNF655 in GECs treated with short hairpin (sh)-LINC00346. However, its function in glioma angiogenesis requires further investigation. Epidermal growth factor-like domain 7 (EGFL7) and Roundabout4 (ROBO4) are both angiogenic factors that are highly expressed in many malignant tumor tissues and cells (e.g., cervical, pancreatic, and breast cancer20Yamauchi M. Fukuda T. Wada T. Kawanishi M. Imai K. Tasaka R. Yasui T. Sumi T. Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer.Oncol. Lett. 2016; 12: 5183-5189Crossref PubMed Scopus (10) Google Scholar, 21Shen X. Han Y. Xue X. Li W. Guo X. Li P. Wang Y. Li D. Zhou J. Zhi Q. Epidermal growth factor-like domain 7 promotes cell invasion and angiogenesis in pancreatic carcinoma.Biomed. Pharmacother. 2016; 77: 167-175Crossref PubMed Scopus (25) Google Scholar, 22Zhao H. Ahirwar D.K. Oghumu S. Wilkie T. Powell C.A. Nasser M.W. Satoskar A.R. Li D.Y. Ganju R.K. Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.Mol. Oncol. 2016; 10: 272-281Crossref PubMed Scopus (28) Google Scholar). EGFL7 and ROBO4 both have been recognized as the biomarkers of tumor angiogenesis. Recent studies have shown that EGFL7 and ROBO4 are both highly expressed in glioma tissues and cells and promote glioma angiogenesis.23Wang F.Y. Kang C.S. Wang-Gou S.Y. Huang C.H. Feng C.Y. Li X.J. EGFL7 is an intercellular EGFR signal messenger that plays an oncogenic role in glioma.Cancer Lett. 2017; 384: 9-18Crossref PubMed Scopus (38) Google Scholar,24Cai H. Xue Y. Li Z. Hu Y. Wang Z. Liu W. Li Z. Liu Y. Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K/AKT and FAK signaling pathways.Cell. Physiol. Biochem. 2015; 35: 1689-1705Crossref PubMed Scopus (39) Google Scholar In the present study, we investigated the expression of ANKHD1, LINC00346, and ZNF655; their interactions in GECs; and their roles in the regulation of glioma angiogenesis. The results of this study may provide new targets for anti-angiogenesis therapy against glioma and new ideas for targeted therapy. Immunofluorescence staining, quantitative real-time PCR and western blot were used to detect the endogenous expression of ANKHD1. ANKHD1 was mainly located in the cytoplasm and was significantly increased in the GEC group (Figure 1A). The mRNA and protein expression levels of ANKHD1 were significantly upregulated in the GEC group (Figures 1B and 1C). A cell counting kit-8 (CCK-8) assay was conducted to determine that overexpression of ANKHD1 significantly increased the viability of GECs, whereas inhibition of ANKHD1 exhibited the opposite results (Figure 1D). A Transwell assay was used to evaluate that overexpression of ANKHD1 significantly increased migrating cell numbers of GECs, whereas inhibition of ANKHD1 exhibited the opposite results (Figure 1E). A Matrigel tube formation assay was conducted to verify that overexpression of ANKHD1 significantly increased relative tube length and number of branches of GECs, whereas inhibition of ANKHD1 exhibited the opposite results (Figure 1F). Further, EGFL7 and ROBO4 protein expression were significantly increased in the pEX-ANKHD1 group, whereas inhibition of ANKHD1 led to a marked decrease (Figures 1G and 1H). With the use of lncRNA microarray analysis and quantitative real-time PCR, we demonstrated that LINC00346 was significantly decreased in GECs treated with sh-ANKHD1 (Figures S1A and S1B) so that we selected LINC00346 for research, for which the change in expression was the most obvious. Fluorescence in situ hybridization (FISH) was used to demonstrate that LINC00346 was mainly located in the cytoplasm and was markedly upregulated in the GEC group (Figure 2A). Further, quantitative real-time PCR was used to detect that LINC00346 was remarkably highly expressed in the GEC group (Figure 2B). In addition, overexpression of LINC00346 significantly promoted the proliferation, migration, and tube formation of GECs, whereas inhibition of LINC00346 showed a prominent inhibitory effect (Figures 2C–2E). In addition, EGFL7 and ROBO4 protein expression was significantly increased in the pEX-LINC00346 group, whereas the protein expression was significantly decreased in the sh-LINC00346 group (Figures 2F and 2G). With the use of bioinformatics databases (RBPmap), we predicted that ANKHD1 might bind to LINC00346. RNA immunoprecipitation (RIP) results showed that the enrichment of LINC00346 was higher in the anti-ANKHD1 group than that in the anti-immunoglobulin G (IgG) group (Figure 3A). Meanwhile, we examined the expression of LINC00346 in GECs transfected with ANKHD1. LINC00346 expression was significantly decreased in the sh-ANKHD1 group (Figure 3B). Besides, the results indicated that there was no significant difference of the relative expression of nascent LINC00346 in pEX-ANKHD1 (Figure 3C). Furthermore, we detected that the half-life of LINC00346 was significantly shortened in sh-ANKHD1, for which GECs were treated with actinomycin D (Figure 3D). Moreover, simultaneous overexpression of ANKHD1 and LINC00346 significantly increased the proliferation, migration, and tube formation of GECs, and simultaneous inhibition of ANKHD1 and LINC00346 showed a prominent inhibitory effect, whereas there were no significant changes in glioma angiogenesis in the pEX-ANKHD1 + sh-LINC00346 group and sh-ANKHD1 + pEX-LINC00346 group (Figures 3E–3G). Further, simultaneous overexpression of ANKHD1 and LINC00346 significantly increased EGFL7 and ROBO4 protein expression, and simultaneous inhibition of ANKHD1 and LINC00346 significantly decreased the protein expression, whereas there were no significant changes in the protein expression in the pEX-ANKHD1 + sh-LINC00346 group and sh-ANKHD1 + pEX-LINC00346 group (Figures 3H and 3I). With the use of mRNA microarray analysis and quantitative real-time PCR, we verified that ZNF655 was significantly increased in GECs treated with sh-linc00346 (Figures S1C and S1D), so that we selected ZNF655 for research. ZNF655 was found to be located in both nucleus and cytoplasm in the cells and was decreased in GECs (Figure 4A). Also, ZNF655 mRNA and protein expression both exhibited low expression levels in GECs (Figures 4B and 4C). Further, overexpression of ZNF655 significantly inhibited the proliferation, migration, and tube formation of GECs, whereas inhibition of ZNF655 showed the opposite results (Figures 4D–4F). Moreover, EGFL7 and ROBO4 protein expression was significantly decreased in the ZNF655+ group, whereas the protein expression was significantly increased in the ZNF655− group (Figures 4G and 4H). With the use of IntaRNA software, we analyzed that ZNF655 mRNA-targeted LINC00346 in a sequence-specific manner in the 3′ UTR. Dual-luciferase gene reporter assays were conducted to demonstrate the interaction between LINC00346 and ZNF655 mRNA. Two putative binding sites were identified in ZNF655 mRNA. The luciferase activity in the ZNF655-wild-type (WT) + LINC00346 group was significantly reduced compared with that in the ZNF655-WT + LINC00346-negative control (NC) group, whereas the luciferase activity in the ZNF655-mutant (Mut) groups were not affected (Figure 5A). However, the luciferase assays ZNF655-WT1 + LINC00346 did not influence the luciferase activity (Figures S2A and S2B). The results support the hypothesis that there is a putative-targeted combination between LINC00346 and ZNF655 mRNA 3′ UTR. RIP and RNA pull-down results further clarified the combination of LINC00346 and ZNF655 mRNA (Figures 5B and 5C). Furthermore, RIP results proved that LINC00346 and ZNF655 mRNA were both combined with STAU1 (Figures 5D and 5E). In addition, the half-life of ZNF655 mRNA was prolonged in GECs, respectively, treated with sh-LINC00346, STAU1−, or UPF1− (Figures 5F–5H). Moreover, immunofluorescence staining was used to detect the observably highly expressed ZNF655 in the sh-LINC00346 group compared with the sh-NC group (Figure 5I). Then, we demonstrated that ZNF655 protein expression was significantly increased in the sh-LINC00346 group (Figure 5J). Besides, ZNF655 protein expression was significantly increased in the STAU1− and UPF1− group, respectively (Figures 5K and 5L). Moreover, ZNF655 protein exhibited a high expression, and the half-life of ZNF655 mRNA was dramatically prolonged in the sh-LINC00346 + STAU1− group (Figures 5M and 5N). The results showed that the proliferation, migration, and tube formation of GECs were significantly increased in the pEX-LINC00346 + ZNF655− group and decreased in the sh-LINC00346 + ZNF655+ group, whereas there were no significant changes in the pEX-LINC00346 + ZNF655+ group and sh-LINC00346 + ZNF655− group (Figures 6A–6C). Besides, the EGFL7 and ROBO4 protein expression was significantly increased in the pEX-LINC00346 + ZNF655− group and decreased in the sh-LINC00346 + ZNF655+ group, whereas there were no significant changes in the protein expression in the pEX-LINC00346 + ZNF655+ group and sh-LINC00346 + ZNF655− group (Figures 6D and 6E). Chromatin immunoprecipitation (ChIP) assays were performed to verify whether ZNF655 could bind to the promoter region of EGFL7, ROBO4, and ANKHD1, respectively. With the search for bioinformatic database Wilmer Bioinformatics, we predicted a potential binding site within the promoter region of EGFL7, ROBO4, and ANKHD1, and the individual putative ZNF655 binding sites were identified by scanning the DNA sequence in the 2,000-bp region upstream and 200-bp region downstream of the transcription start site (TSS). In the meantime, we respectively amplified the 1,000-bp-upstream region of the individual putative ZNF655 binding sites on EGFL7, ROBO4, and ANKHD1 as the corresponding negative control. The results demonstrated that there was a direct association of ZNF655 with the putative binding site of EGFL7, the putative binding site of ROBO4, and the putative binding site of ANKHD1, respectively, whereas there was no association of ZNF655 with all of the control regions (Figures 7A–7C). Also, we used quantitative real-time PCR to, respectively, detect the relative DNA enrichment of EGFL7, ROBO4, and, ANKHD1 (Figure 7D). Meanwhile, luciferase reporter assays verified that ZNF655 inhibited the transcription of EGFL7, ROBO4, and ANKHD1 by binding to their promoter region, respectively (Figures 7E–7G). In addition, EGFL7, ROBO4, and ANKHD1 mRNA expression was significantly decreased in the ZNF655+ group compared with the ZNF655+-NC group, whereas the opposite results were shown in the ZNF655− group (Figures 7H–7J). Besides, overexpression of ZNF655 significantly decreased ANKHD1 protein expression (Figure 7K). Further, ZNF655 protein expression was significantly decreased in the pEX-ANKHD1 group, whereas inhibition of ANKHD1 led to a marked increase (Figure 7L). Also, there were no significant changes in the protein expression of ZNF655 in the pEX-ANKHD1 + sh-LINC00346 group and sh-ANKHD1 + pEX-LINC00346 group (Figure 7M). Matrigel plug assay was conducted to further evaluate the glioma angiogenesis in vivo. As shown in Figures 8A and 8B , the amount of hemoglobin in the sh-ANKHD1 group, sh-LINC00346 group, ZNF655+ group, and sh-ANKHD1 + sh-LINC00346 + ZNF655+ group was significantly decreased compared with the control group. At the same time, the amount of hemoglobin in the sh-ANKHD1 + sh-LINC00346 + ZNF655+ group exerted a marked decrease compared with the sh-ANKHD1 group, sh-LINC00346 group, and ZNF655+ group, respectively. These results demonstrate that with the combination of ANKHD1 knockdown, LINC00346 knockdown, and ZNF655 overexpression present, the more prominent inhibitory effect on glioma angiogenesis in vivo. In this study, we demonstrated that ANKHD1 was upregulated in GECs. The knockdown of ANKHD1 impeded the GEC proliferation, migration, and tube formation. ANKHD1 enhanced the stability of LINC00346 and increased its expression. Inhibition of ANKHD1 shortened the half-life of LINC00346, which was normally expressed at high levels in GECs. The knockdown of LINC00346 inhibited the angiogenesis of GECs. In addition, ANKHD1 targeted LINC00346, and overexpression of LINC00346 reversed the inhibitory effect of silencing ANKHD1 in the regulation of glioma angiogenesis. ZNF655 exhibited low expression levels in GECs. ZNF655 overexpression suppressed GEC proliferation, migration, and tube formation. LINC00346 specifically bound to ZNF655 mRNA via their Alu elements. Furthermore, we found that LINC00346 facilitated the degradation of ZNF655 mRNA via SMD and regulated the angiogenesis of GECs. Moreover, ZNF655 targeted the promoter region of ANKHD1, inhibited transcription, and formed an ANKHD1/LINC00346/ZNF655 feedback loop that regulated glioma angiogenesis. In the present study, we found, for the first time, that ANKHD1 was expressed at high levels in GECs. Recent studies have indicated that RBPs play a role in regulating tumor development. For example, SRSF6 is upregulated in colorectal cancer (CRC) samples and cell lines. High SRSF6 expression promotes CRC cell proliferation metastasis in vitro and in vivo.25Wan L. Yu W. Shen E. Sun W. Liu Y. Kong J. Wu Y. Han F. Zhang L. Yu T. et al.SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer.Gut. 2019; 68: 118-129Crossref PubMed Scopus (77) Google Scholar ANKHD1 is highly expressed in human prostate and breast cancer and significantly reduces patient survival time.26Machado-Neto J.A. Lazarini M. Favaro P. Franchi Jr., G.C. Nowill A.E. Saad S.T. Traina F. ANKHD1, a novel component of the Hippo signaling pathway, promotes YAP1 activation and cell cycle progression in prostate cancer cells.Exp. Cell Res. 2014; 324: 137-145Crossref PubMed Scopus (37) Google Scholar,27Sansores-Garcia L. Atkins M. Moya I.M. Shahmoradgoli M. Tao C. Mills G.B. Halder G. Mask is required for the activity of the Hippo pathway effector Yki/YAP.Curr. Biol. 2013; 23: 229-235Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar However, the function of ANKHD1 in glioma and in regulating GECs is still unclear. In this study, inhibition of ANKHD1 significantly suppressed the proliferation, migration, and tube formation of GECs and reduced the expression of EGFL7 and ROBO4, which are the biomarkers of tumor angiogenesis. This indicated that ANKHD1 promoted angiogenesis of GECs. The above research results indicate that ANKHD1, which is highly expressed in GECs, plays an oncogenic role in regulating angiogenesis of glioma. Further, we explored the target genes that were directly regulated by ANKHD1. The microarray analysis results showed that LINC00346 was significantly decreased in GECs after downregulation of ANKHD1. Accumulating evidence has demonstrated that lncRNA is abnormally expressed in many malignant tumors and serves as a molecular marker in the diagnosis and treatment of cancer.28Xu T. Yan S. Jiang L. Yu S. Lei T. Yang D. Lu B. Wei C. Zhang E. Wang Z. Gene Amplification-Driven Long Noncoding RNA SNHG17 Regulates Cell Proliferation and Migration in Human Non-Small-Cell Lung Cancer.Mol. Ther. Nucleic Acids. 2019; 17: 405-413Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 29Tiessen I. Abildgaard M.H. Lubas M. Gylling H.M. Steinhauer C. Pietras E.J. Diederichs S. Frankel L.B. Lund A.H. A high-throughput screen identifies the long non-coding RNA DRAIC as a regulator of autophagy.Oncogene. 2019; 38: 5127-5141Crossref PubMed Scopus (26) Google Scholar, 30Dolcino M. Tinazzi E. Puccetti A. Lunardi C. In Systemic Sclerosis, a Unique Long Non Coding RNA Regulates Genes and Pathways Involved in the Three Main Features of the Disease (Vasculopathy, Fibrosis and Autoimmunity) and in Carcinogenesis.J. Clin. Med. 2019; 8: 320Crossref Scopus (20) Google Scholar Studies have shown that the upregulated expression of LINC00346 in non-small cell lung cancer promotes the cell proliferation, whereas inhibits the apoptosis.31Wang F. Chen J.G. Wang L.L. Yan Z.Z. Chen S.P. Wang X.G. Up-regulation of LINC00346 inhibits proliferation of non-small cell lung cancer cells through mediating JAK-STAT3 signaling pathway.Eur. Rev. Med. Pharmacol. Sci. 2017; 21: 5135-5142PubMed Google Scholar However, there has not been any research about the expression and function of LINC00346 in glioma angiogenesis. The results from The Cancer Genome Atlas (TCGA) database analysis indicated that LINC00346 is highly expressed in glioma tissues, and the expression of LINC00346 is significantly, positively correlated with the poor prognosis of glioma patients. In this study, we found that LINC00346 was also highly expressed in GECs. The knockdown of LINC00346 inhibited GEC proliferation, migration, and tube formation. Our results suggest that LINC00346 acts as an oncogene in glioma, and inhibition of LINC00346 may abrogate glioma angiogenesis. In the meantime, we detected that knockdown of ANKHD1 significantly inhibited the expression of LINC00346 in GECs. Thus, the above results indicated that ANKHD1 facilitated glioma angiogenesis by regulating LINC00346. However, the molecular mechanism by which ANKHD1 regulates LINC00346 during the angiogenesis associated with glioma is still unclear; therefore, the specific mechanism has attracted our attention. In the present study, we demonstrated that the silencing of ANKHD1 in GECs significantly reduced the half-life of LINC00346, but there was no significant difference for the relative expression of nascent LINC00346 in pEX-ANKHD1. With the use of RBPmap bioinformatics software, we detected a binding site between ANKHD1 and LINC00346. Meanwhile, RIP results revealed that ANKHD1 bound to LINC00346. The biological role of this complex is carried out through its binding to the Ago2 protein of the RNA-induced silencing complex (RISC). These exploratory findings indicate that ANKHD1 promotes the expression of LINC00346 by increasing the stability of LINC00346. Studies have shown that RBP dysregulation, which regulates several vital processes, such as splicing and translation of lncRNAs, enhances the stability of lncRNAs, increasing lncRNAs expression, and regulates the malignant behavior of tumors.32Tichon A. Perry R.B. Stojic L. Ulitsky I. SAM68 is required for regulation of Pumilio by the NORAD long noncoding RNA.Genes Dev. 2018; 32: 70-78Crossref PubMed Scopus (45) Google Scholar,33Liu X. Zheng J. Xue Y. Qu C. Chen J. Wang Z. Li Z. Zhang L. Liu Y. Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells.Mol. Ther. Nucleic Acids. 2018; 10: 142-158Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Furthermore, we detected that there were no significant changes in GEC proliferation, migration, and tube formation following overexpression of ANKHD1 combined with inhibition of L" @default.
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• W3025004947 title "Role of ANKHD1/LINC00346/ZNF655 Feedback Loop in Regulating the Glioma Angiogenesis via Staufen1-Mediated mRNA Decay" @default.
• W3025004947 cites W1972026067 @default.
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