1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, China
2. Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, China
3. The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China
denglinqilu@163.com
dr.ligang@sdu.edu.cn
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History+
Received
Accepted
Published Online
2021-03-18
2022-04-21
2022-08-30
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(8259KB)
Abstract
Gliomas are the most common central nervous system tumours; they are highly aggressive and have a poor prognosis. RGS16 belongs to the regulator of G-protein signalling (RGS) protein family, which plays an important role in promoting various cancers, such as breast cancer, pancreatic cancer, and colorectal cancer. Moreover, previous studies confirmed that let-7c-5p, a well-known microRNA, can act as a tumour suppressor to regulate the progression of various tumours by inhibiting the expression of its target genes. However, whether RGS16 can promote the progression of glioma and whether it is regulated by miR let-7c-5p are still unknown. Here, we confirmed that RGS16 is upregulated in glioma tissues and that high expression of RGS16 is associated with poor survival. Ectopic deletion of RGS16 significantly suppressed glioma cell proliferation and migration both in vitro and in vivo. Moreover, RGS16 was validated as a direct target gene of miR let-7c-5p. The overexpression of miR let-7c-5p obviously downregulated the expression of RGS16, and knocking down miR let-7c-5p had the opposite effect. Thus, we suggest that the suppression of RGS16 by miR let-7c-5p can promote glioma progression and may serve as a potential prognostic biomarker and therapeutic target in glioma.
Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, Agarwalla PK, Chheda MG, Campos B, Wang A, Brennan C, Ligon KL, Furnari F, Cavenee WK, Depinho RA, Chin L, Hahn WC. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev2012; 26(8): 756–784
[2]
Villa C, Miquel C, Mosses D, Bernier M, Di Stefano AL. The 2016 World Health Organization classification of tumours of the central nervous system. Presse Med2018; 47(11–12): e187–e200
[3]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin2018; 68(6): 394–424
[4]
Chen J, McKay RM, Parada LF. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell2012; 149(1): 36–47
[5]
Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem2000; 69(1): 795–827
[6]
Druey KM, Blumer KJ, Kang VH, Kehrl JH. Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Nature1996; 379(6567): 742–746
[7]
Liang G, Bansal G, Xie Z, Druey KM. RGS16 inhibits breast cancer cell growth by mitigating phosphatidylinositol 3-kinase signaling. J Biol Chem2009; 284(32): 21719–21727
[8]
Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TL, Brown JH, Druey KM. RGS16 inhibits signalling through the G alpha 13-Rho axis. Nat Cell Biol2003; 5(12): 1095–1103
[9]
Berthebaud M, Rivière C, Jarrier P, Foudi A, Zhang Y, Compagno D, Galy A, Vainchenker W, Louache F. RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. Blood2005; 106(9): 2962–2968
[10]
Carper MB, Denvir J, Boskovic G, Primerano DA, Claudio PP. RGS16, a novel p53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells. Genes Cancer2014; 5(11–12): 420–435
[11]
Miyoshi N, Ishii H, Sekimoto M, Doki Y, Mori M. RGS16 is a marker for prognosis in colorectal cancer. Ann Surg Oncol2009; 16(12): 3507–3514
[12]
Sun X, Charbonneau C, Wei L, Chen Q, Terek RM. miR-181a targets RGS16 to promote chondrosarcoma growth, angiogenesis, and metastasis. Mol Cancer Res2015; 13(9): 1347–1357
[13]
Sayed D, Abdellatif M. MicroRNAs in development and disease. Physiol Rev2011; 91(3): 827–887
[14]
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer2006; 6(11): 857–866
[15]
Fu X, Mao X, Wang Y, Ding X, Li Y. Let-7c-5p inhibits cell proliferation and induces cell apoptosis by targeting ERCC6 in breast cancer. Oncol Rep2017; 38(3): 1851–1856
[16]
Huang M, Gong X. Let-7c inhibits the proliferation, invasion, and migration of glioma cells via targeting E2F5. Oncol Res2018; 26(7): 1103–1111
[17]
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med2008; 359(5): 492–507
[18]
Huang R, Li G, Zhao Z, Zeng F, Zhang K, Liu Y, Wang K, Hu H. RGS16 promotes glioma progression and serves as a prognostic factor. CNS Neurosci Ther2020; 26(8): 791–803
[19]
Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, Sun P, Tan CK, Hengst L, Slingerland J. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell2007; 128(2): 281–294
[20]
Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS. Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res2003; 63(11): 2742–2746
[21]
Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y, Wang Y, Chopp M. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci2006; 26(22): 5996–6003
[22]
Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, Shokat KM, Weiss WA. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal2010; 3(147): ra81
[23]
Suzuki Y, Shirai K, Oka K, Mobaraki A, Yoshida Y, Noda SE, Okamoto M, Suzuki Y, Itoh J, Itoh H, Ishiuchi S, Nakano T. Higher pAkt expression predicts a significant worse prognosis in glioblastomas. J Radiat Res (Tokyo)2010; 51(3): 343–348
[24]
Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS. Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res2003; 63(11): 2742–2746
[25]
Mure H, Matsuzaki K, Kitazato KT, Mizobuchi Y, Kuwayama K, Kageji T, Nagahiro S. Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro-oncol2010; 12(3): 221–232
[26]
Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell2017; 31(3): 326–341
Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer2006; 6(4): 259–269
[29]
Piwecka M, Rolle K, Belter A, Barciszewska AM, Żywicki M, Michalak M, Nowak S, Naskręt-Barciszewska MZ, Barciszewski J. Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol2015; 9(7): 1324–1340