Similar articles

Abstract: hypoxia, as an important hallmark of the tumor microenvironment, is a major cause of oxidative stress and plays a central role in various malignant tumors, including glioblastoma. Elevated )%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>reactive oxygen species (ROS) in a hypoxic microenvironment promote glioblastoma progression; however, the underlying mechanism has not been clarified. Herein, we found that hypoxia promoted ROS production, and the proliferation, migration, and invasion of glioblastoma cells, while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine (NAC) and diphenyleneiodonium chloride (DPI). hypoxia-induced ROS activated hypoxia-inducible factor-1α (HIF-1α;) signaling, which enhanced cell migration and invasion by epithelial-mesenchymal transition (EMT). Furthermore, the induction of serine protease inhibitor family E member 1 (SERPINE1) was ROS-dependent under hypoxia, and HIF-1α mediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region, thereby facilitating glioblastoma migration and invasion. Taken together, our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway, and that targeting ROS may be a promising therapeutic strategy for glioblastoma.

缺氧诱导的ROS通过HIF-1α-SERPINE1信号通路促进胶质母细胞瘤恶性进展

[1]AndrewAS, KleiLR, BarchowskyA, 2001. Nickel requires hypoxia-inducible factor-1α, not redox signaling, to induce plasminogen activator inhibitor-1. Am J Physiol Lung Cell Mol Physiol, 281(3):L607-L615.

[2]AzimiI, PetersenRM, ThompsonEW, et al., 2017. Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells. Sci Rep, 7:15140.

[3]CarreresL, Mercey-RessejacM, KurmaK, et al., 2022. Chronic intermittent hypoxia increases cell proliferation in hepatocellular carcinoma. Cells, 11(13):2051.

[4]ChandelNS, MaltepeE, GoldwasserE, et al., 1998. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA, 95(20):‍11715-11720.

[5]ChandelNS, McClintockDS, FelicianoCE, et al., 2000. React

[6]ive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O₂ sensing. J Biol Chem, 275(33):25130-25138.

[7]ChédevilleAL, LourdusamyA, MonteiroAR, et al., 2020. Investigating glioblastoma response to hypoxia. Biomedicines, 8(9):310.

[8]ChenCL, WangSC, LiuP, 2019. Deferoxamine enhanced mitochondrial iron accumulation and promoted cell migration in triple-negative MDA-MB-231 breast cancer cells via a ROS-dependent mechanism. Int J Mol Sci, 20(19):4852.

[9]ChenD, WuYX, QiuYB, et al., 2020. Hyperoside suppresses hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis. Phytomedicine, 67:153138.

[10]ChenXT, LiZW, YongHM, et al., 2021. Trim21-mediated HIF-1α degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis. Cancer Lett, 508:115-126.

[11]ChiuJ, DawesIW, 2012. Redox control of cell proliferation. Trends Cell Biol, 22(11):592-601.

[12]ChuaYL, DufourE, DassaEP, et al., 2010. Stabilization of hypoxia-inducible factor-1α protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. J Biol Chem, 285(41):31277-31284.

[13]DabralS, MueckeC, ValasarajanC, et al., 2019. A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun, 10:2130.

[14]Dao TrongP, RöschS, MairbäurlH, et al., 2018. Identification of a prognostic hypoxia-associated gene set in IDH-mutant glioma. Int J Mol Sci, 19(10):2903.

[15]DröseS, 2013. Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning. Biochim Biophys Acta Bioenerget, 1827(5):578-587.

[16]FandreyJ, Gassmann M, 2009. Oxygen sensing and the activation of the hypoxia inducible factor 1 (HIF-1)‍‒‍Invited Article. In: Gonzalez C, Nurse CA, Peers C (Eds.), Arterial Chemoreceptors. Advances in Experimental Medicine and Biology, Vol. 648. Springer, Dordrecht, p.197-206.

[17]FinkT, KazlauskasA, PoellingerL, et al., 2002. Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood, 99(6):2077-2083.

[18]GeWJ, ZhaoKM, WangXW, et al., 2017. iASPP is an antioxidative factor and drives cancer growth and drug resistance by competing with Nrf2 for Keap1 binding. Cancer Cell, 32(5):561-573.6.

[19]HarrisAL, 2002. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer, 2(1):38-47.

[20]HouP, ZhaoY, LiZ, et al., 2014. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis, 5(6):e1287.

[21]HuZZ, DongN, LuD, et al., 2017. A positive feedback loop between ROS and Mxi1-0 promotes hypoxia-induced VEGF expression in human hepatocellular carcinoma cells. Cell Signal, 31:79-86.

[22]HumphriesBA, BuschhausJM, ChenYC, et al., 2019. Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer. Mol Cancer Res, 17(5):‍1142-1154.

[23]HurdTR, DeGennaroM, LehmannR, 2012. Redox regulation of cell migration and adhesion. Trends Cell Biol, 22(2):107-115.

[24]IvanM, KaelinWG, 2017. The EGLN-HIF O₂-sensing system: multiple inputs and feedbacks. Mol Cell, 66(6):772-779.

[25]JinP, ShinSH, ChunYS, et al., 2018. Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-‍κB signaling pathway. Oncogene, 37(23):3070-3087.

[26]KeQD, CostaM, 2006. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol, 70(5):1469-1480.

[27]KesslerJ, HahnelA, WichmannH, et al., 2010. HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer, 10:605.

[28]KlimovaT, ChandelNS, 2008. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ, 15(4):660-666.

[29]KunschC, MedfordRM, 1999. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res, 85(8):753-766.

[30]LeiJJ, HuoXW, DuanWX, et al., 2014. α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion. Cancer Lett, 347(1):129-138.

[31]LiSJ, WeiXH, ZhanXM, et al., 2020. Adipocyte-derived leptin promotes PAI-1-mediated breast cancer metastasis in a STAT3/miR-34a dependent manner. Cancers (Basel), 12(12):3864.

[32]LiX, WuP, TangYY, et al., 2020. Down-regulation of miR-181c-5p promotes epithelial-to-mesenchymal transition in laryngeal squamous cell carcinoma via targeting SERPINE1. Front Oncol, 10:544476.

[33]LiX, ZuoHW, ZhangL, et al., 2021. Validating HMMR expression and its prognostic significance in lung adenocarcinoma based on data mining and bioinformatics methods. Front Oncol, 11:720302.

[34]LiXD, DongP, WeiWS, et al., 2019. Overexpression of CEP72 promotes bladder urothelial carcinoma cell aggressiveness via epigenetic CREB-mediated induction of SERPINE1. Am J Pathol, 189(6):1284-1297.

[35]LiZW, HouPF, FanDM, et al., 2017. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ, 24(1):59-71.

[36]LiuL, XiaoS, WangY, et al., 2022. Identification of a novel circular RNA circZNF652/miR-486-5p/SERPINE1 signaling cascade that regulates cancer aggressiveness in glioblastoma (GBM). Bioengineered, 13(1):1411-1423.

[37]LuW, KangYB, 2019. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell, 49(3):‍361-374.

[38]LukyanovaLD, KirovaYI, GermanovaEL, 2018. The role of succinate in regulation of immediate HIF-1α expression in hypoxia. Bull Exp Biol Med, 164(3):298-303.

[39]MittalM, GuXQ, PakO, et al., 2012. Hypoxia induces K_v channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med, 52(6):1033-1042.

[40]Miyashita-IshiwataM, el SabehM, ReschkeLD, et al., 2022. Hypoxia induces proliferation via NOX4-mediated oxidative stress and TGF-β3 signaling in uterine leiomyoma cells. Free Radic Res, 56(2):163-172.

[41]MonteiroAR, HillR, PilkingtonGJ, et al., 2017. The role of hypoxia in glioblastoma invasion. Cells, 6(4):45.

[42]NiecknigH, TugS, ReyesBD, et al., 2012. Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res, 46(6):705-717.

[43]OlarA, AldapeKD, 2014. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol, 232(2):165-177.

[44]OmuroA, DeAngelisLM, 2013. Glioblastoma and other malignant gliomas: a clinical review. JAMA, 310(17):1842-1850.

[45]PengPH, LaiJCY, HsuKW, et al., 2020. Hypoxia-induced lncRNA RP11-390F4.3 promotes epithelial-mesenchymal transition (EMT) and metastasis through upregulating EMT regulators. Cancer Lett, 483:35-45.

[46]PerilloB, di DonatoM, PezoneA, et al., 2020. ROS in cancer therapy: the bright side of the moon. Exp Mol Med, 52(2):192-203.

[47]PolyakK, WeinbergRA, 2009. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer, 9(4):265-273.

[48]QuinlanCL, OrrAL, PerevoshchikovaIV, et al., 2012. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem, 287(32):27255-27264.

[49]SchieberM, ChandelNS, 2014. ROS function in redox signaling and oxidative stress. Curr Biol, 24(10):R453-R462.

[50]SchumackerPT, 2011. SIRT3 controls cancer metabolic reprogramming by regulating ROS and HIF. Cancer Cell, 19(3):299-300.

[51]SemenzaGL, 1998. Hypoxia-inducible factor 1: master regulator of O₂ homeostasis. Curr Opin Genet Dev, 8(5):588-594.

[52]SemenzaGL, 2014. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol Mech Dis, 9:47-71.

[53]SpencerNY, EngelhardtJF, 2014. The basic biology of redoxosomes in cytokine-mediated signal transduction and implications for disease-specific therapies. Biochemistry, 53(10):1551-1564.

[54]SrivastavaC, IrshadK, DikshitB, et al., 2018. FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma. Int J Cancer, 142(4):805-812.

[55]SubramanianA, TamayoP, MoothaVK, et al., 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA, 102(43):15545-15550.

[56]SunB, YuL, XuC, et al., 2021. NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma. Cancer Sci, 112(7):2753-2769.

[57]TakayamaY, HattoriN, HamadaH, et al., 2016. Inhibition of PAI-1 limits tumor angiogenesis regardless of angiogenic stimuli in malignant pleural mesothelioma. Cancer Res, 76(11):3285-3294.

[58]TangZH, ZhangZH, LinQQ, et al., 2021. HIF-1α/BNIP3-mediated autophagy contributes to the luteinization of granulosa cells during the formation of corpus luteum. Front Cell Dev Biol, 8:619924.

[59]TengF, ZhangJX, ChenY, et al., 2021. LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer. Mol Oncol, 15(4):1234-1255.

[60]ThieryJP, AcloqueH, HuangRYJ, et al., 2009. Epithelial-mesenchymal transitions in development and disease. Cell, 139(5):871-890.

[61]TsaiJH, YangJ, 2013. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev, 27(20):2192-2206.

[62]VordermarkD, 2005. Significance of hypoxia in malignant glioma. Re: Evanset al. Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 2004;10:8177-84. Clin Cancer Res, 11(10):3966-3968.

[63]WangQ, LuWJ, YinT, et al., 2019. Calycosin suppresses TGF-‍β‍-induced epithelial-to-mesenchymal transition and migration by upregulating BATF2 to target PAI-1 via the Wnt and PI3K/Akt signaling pathways in colorectal cancer cells. J Exp Clin Cancer Res, 38:240.

[64]WangXW, BustosMA, ZhangXQ, et al., 2020. Downregulation of the ubiquitin-E3 ligase RNF123 promotes upregulation of the NF‍-‍κB1 target SerpinE1 in aggressive glioblastoma tumors. Cancers (Basel), 12(5):1081.

[65]WangZL, ShiYP, YingCT, et al., 2021. Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via NF‍-‍κB signaling. Oncogene, 40(8):1458-1475.

[66]WatsonJ, 2013. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol, 3(1):120144.

[67]WeidemannA, JohnsonRS, 2008. Biology of HIF-1α. Cell Death Differ, 15(4):621-627.

[68]WillsonJA, ArientiS, SadikuP, et al., 2022. Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle. Blood, 139(2):281-286.

[69]WilsonWR, HayMP, 2011. Targeting hypoxia in cancer therapy. Nat Rev Cancer, 11(6):393-410.

[70]WuK, MaoYY, ChenQ, et al., 2021. Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma. Cell Oncol (Dordr), 44(5):‍1167-1181.

[71]XiaLM, MoP, HuangWJ, et al., 2012. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis, 33(11):2250-2259.

[72]XuBD, BaiZG, YinJ, et al., 2019. Global transcriptomic analysis identifies SERPINE1 as a prognostic biomarker associated with epithelial-to-mesenchymal transition in gastric cancer. PeerJ, 7:e7091.

[73]XuYQ, ChenWC, LiangJ, et al., 2021. The miR-1185-2-3p-GOLPH3L pathway promotes glucose metabolism in breast cancer by stabilizing p53-induced SERPINE1. J Exp Clin Cancer Res, 40:47.

[74]YangJ, AntinP, BerxG, et al., 2020. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol, 21(6):341-352.

[75]YangJL, MaQ, ZhangMM, et al., 2021. LncRNA CYTOR drives L-OHP resistance and facilitates the epithelial-mesenchymal transition of colon carcinoma cells via modulating miR-378a-5p/SERPINE1. Cell Cycle, 20(14):1415-1430.

[76]YangY, ZhangGM, GuoFZ, et al., 2020. Mitochondrial UQCC3 modulates hypoxia adaptation by orchestrating OXPHOS and glycolysis in hepatocellular carcinoma. Cell Rep, 33(5):108340.

[77]YuLM, ZhangWH, HanXX, et al., 2019. Hypoxia-induced ROS contribute to myoblast pyroptosis during obstructive sleep apnea via the NF‍-‍κB/HIF‍-‍1αsignaling pathway. Oxid Med Cell Longev, 2019:4596368.

[78]ZhangW, ZhangYW, ZhouWS, et al., 2021. PlGF knockdown attenuates hypoxia-induced stimulation of cell proliferation and glycolysis of lung adenocarcinoma through inhibiting Wnt/β‍-catenin pathway. Cancer Cell Int, 21:18.

[79]ZhangYS, JinGS, ZhangJW, et al., 2018. Overexpression of STAT1 suppresses angiogenesis under hypoxia by regulating VEGF-A in human glioma cells. Biomed Pharmacother, 104:566-575.

[80]ZhaoQ, ZhangLW, HeQF, et al., 2023. Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 24(1):50-63.

[81]ZhengH, KangY, 2014. Multilayer control of the EMT master regulators. Oncogene, 33(14):1755-1763.

[82]ZongSQ, TangYF, LiW, et al., 2020. A Chinese herbal formula suppresses colorectal cancer migration and vasculogenic mimicry through ROS/HIF-1α/MMP2 pathway in hypoxic microenvironment. Front Pharmacol, 11:705.