Abstract
Angiogenesis is required for tumor progression; thus, its investigation can be useful to identify strategies for potential cancer treatments. Tripartite motif 47 (TRIM47) is involved in the progression of multiple cancers. However, its role in glioma angiogenesis is largely unknown. In this study, we first showed that TRIM47 is frequently upregulated in gliomas, and increased TRIM47 levels are correlated with microvascular density. We then examined the role of TRIM47 in cellular functions related to angiogenesis in vitro and observed that TRIM47 knockdown significantly reduced human umbilical vein endothelial cell proliferation, migration, and tube formation. We also found that TRIM47 silencing reduced vessel density and tumor volume in glioma xenografts. Mechanistically, TRIM47 negatively regulated Smad4 expression in glioma cells, and SMAD4 knockdown rescued the suppressive effects of TRIM47 silencing. Taken together, our results indicate that TRIM47 promotes angiogenesis in gliomas by downregulating SMAD4. Therefore, targeting the TRIM47/SMAD4 axis may offer an innovative approach to glioma treatment.
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The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants, but are available on reasonable request from the corresponding author.
References
Ahmed S, Bradshaw AD, Gera S, Dewan MZ, and Xu R (2017) The TGF-beta/Smad4 signaling pathway in pancreatic carcinogenesis and its clinical significance. J Clin Med 6
Bello L, Giussani C, Carrabba G, Pluderi M, Costa F, Bikfalvi A (2004) Angiogenesis and invasion in gliomas. Cancer Treat Res 117:263–284
Chang HW, Wang WD, Chiu CC, Chen CH, Wang YS, Chen ZY, Liu W, Tai MH, Wen ZH, and Wu CY (2017) Ftr82 is critical for vascular patterning during zebrafish development. Int J Mol Sci 18
Chen L, Li M, Li Q, Xu M, Zhong W (2020) Knockdown of TRIM47 inhibits glioma cell proliferation, migration and invasion through the inactivation of Wnt/beta-catenin pathway. Mol Cell Probes 53:101623
Chen R, Smith-Cohn M, Cohen AL, Colman H (2017) Glioma subclassifications and their clinical significance. Neurotherapeutics 14:284–297
Crist AM, Lee AR, Patel NR, Westhoff DE, Meadows SM (2018) Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of hereditary hemorrhagic telangiectasia. Angiogenesis 21:363–380
Delgado-Lopez PD, Corrales-Garcia EM (2016) Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18:1062–1071
Han Y, Tian H, Chen P, Lin Q (2017) TRIM47 overexpression is a poor prognostic factor and contributes to carcinogenesis in non-small cell lung carcinoma. Oncotarget 8:22730–22740
Hatakeyama S (2011) TRIM proteins and cancer. Nat Rev Cancer 11:792–804
Hatakeyama S (2017) TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci 42:297–311
He Q, Zhao L, Liu X, Zheng J, Liu Y, Liu L, Ma J, Cai H, Li Z, Xue Y (2019) 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 38:9
Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD, Hoshyar R, Seyfoori A, Sepehri Z, Ande SR, Khadem F, Akbari M, Gorman AM, Samali A, Klonisch T, Ghavami S (2018) Glioblastoma and chemoresistance to alkylating agents: involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184:13–41
Jain RK, Di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622
Jaworska AM, Wlodarczyk NA, Mackiewicz A, Czerwinska P (2020) The role of TRIM family proteins in the regulation of cancer stem cell self-renewal. Stem Cells 38:165–173
Ji B, Liu L, Guo Y, Ming F, Jiang J, Li F, Zhao G, Wen J, Li N (2021) Upregulated tripartite motif 47 could facilitate glioma cell proliferation and metastasis as a tumorigenesis promoter. Comput Math Methods Med 2021:5594973
Li WJ, Wang Y, Liu R, Kasinski AL, Shen H, Slack FJ, Tang DG (2021) MicroRNA-34a: potent tumor suppressor, cancer stem cell inhibitor, and potential anticancer therapeutic. Front Cell Dev Biol 9:640587
Liang Q, Tang C, Tang M, Zhang Q, Gao Y, Ge Z (2019) TRIM47 is up-regulated in colorectal cancer, promoting ubiquitination and degradation of SMAD4. J Exp Clin Cancer Res 38:159
Liang W, Guo B, Ye J, Liu H, Deng W, Lin C, Zhong X, Wang L (2019) Vasorin stimulates malignant progression and angiogenesis in glioma. Cancer Sci 110:2558–2572
Mi S, Du J, Liu J, Hou K, Ji H, Ma S, Ba Y, Chen L, Xie R, Hu S (2020) FtMt promotes glioma tumorigenesis and angiogenesis via lncRNA SNHG1/miR-9-5p axis. Cell Signal 75:109749
Omuro A, Deangelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850
Schwarte-Waldhoff I, Schmiegel W (2002) Smad4 transcriptional pathways and angiogenesis. Int J Gastrointest Cancer 31:47–59
Tuettenberg J, Friedel C, Vajkoczy P (2006) Angiogenesis in malignant glioma–a target for antitumor therapy? Crit Rev Oncol Hematol 59:181–193
Vandeputte DA, Meije CB, Van Dartel M, Leenstra S, IJIst-Keizers H, Das PK, Troost D, Bosch DA, Baas F, Hulsebos TJ (2001) GOA, a novel gene encoding a ring finger B-box coiled-coil protein, is overexpressed in astrocytoma. Biochem Biophys Res Commun 286:574–579
Venuto S, and Merla G (2019) E3 ubiquitin ligase TRIM proteins, cell cycle and mitosis. Cells 8
Wang J, Li Y, Zhou JH, Shen FR, Shi X, Chen YG (2021) CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR-378. Mol Oncol 15:1217–1233
Wang Y, Li J, Huang Y, Dai X, Liu Y, Liu Z, Wang Y, Wang N, Zhang P (2017) Tripartite motif-containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR-1 and -2 and VEGFR2 in endothelial cells. FASEB J 31:2026–2036
Wang Y, Liu C, Xie Z, Lu H (2020) Knockdown of TRIM47 inhibits breast cancer tumorigenesis and progression through the inactivation of PI3K/Akt pathway. Chem Biol Interact 317:108960
Wei H, Ding C, Zhuang H, Hu W (2020) TRIM47 promotes the development of glioma by ubiquitination and degradation of FOXO1. Onco Targets Ther 13:13401–13411
Yan C, Wang J, Yang Y, Ma W, Chen X (2019) Molecular biomarker-guided anti-angiogenic targeted therapy for malignant glioma. J Cell Mol Med 23:4876–4882
Yang J, Wang Y, Zeng Z, Qiao L, Zhuang L, Gao Q, Ma D, Huang X (2017) Smad4 deletion in blood vessel endothelial cells promotes ovarian cancer metastasis. Int J Oncol 50:1693–1700
Zhang B, Zhang B, Chen X, Bae S, Singh K, Washington MK, Datta PK (2014) Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway. Br J Cancer 110:946–957
Zhou G, Wu H, Lin J, Lin R, Feng B, Liu Z (2021) TRIM21 is decreased in colitis-associated cancer and negatively regulates epithelial carcinogenesis. Inflamm Bowel Dis 27:458–468
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KW, ZW, and ZL conceived and designed the study. KW, ZW, CH, and YC performed the experiment and collected, analyzed, and interpreted the data. KW wrote the manuscript. KW and ZL revised the manuscript. All of the authors read and approved the final manuscript.
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Informed consent was obtained from all individual participants included in the study. All procedures were approved by the Ethics Committee of the Central Hospital of Fengxian District and operated in keeping with the standards set out in the Announcement of Helsinki and laboratory guidelines of research in China.
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Wang, Z., Li, Z., Han, C. et al. TRIM47 promotes glioma angiogenesis by suppressing Smad4. In Vitro Cell.Dev.Biol.-Animal 58, 771–779 (2022). https://doi.org/10.1007/s11626-022-00722-6
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DOI: https://doi.org/10.1007/s11626-022-00722-6