缺氧诱导因子在胶质瘤细胞上皮-间质转化过程中对细胞迁移和侵袭影响的研究进展

doi:10.13481/j.1671-587X.20250432

Abstract

Abstract:

Epithelial-mesenchymal transition （EMT） is a critical process in the development of various cancers， including glioma. In glioma cells， the activation of hypoxia-inducible factors （HIFs） can influence the occurrence of EMT， promoting cell migration and invasion. This review aims to explore the role of HIF in the EMT process of glioma cells， focusing on its impact on cell migration and invasion， including regulation of angiogenesis， metabolic reprogramming， glycolysis， and the immune system in the tumor microenvironment. Additionally， this review summarizes the role of HIF in EMT-related signaling pathways， such as Wnt/β-catenin （β-catenin）， Notch， and transforming growth factor-β （TGF-β）， and provides new insights and directions for further understanding the mechanisms of HIF in the EMT process of glioma cells.

Key words: Hypoxia-inducible factor, Glioma, Epithelial-mesenchymal transition, Cell migration, Cell invasion

CLC Number:

R739.41

Zhongjun SHEN,Yao ZHAO,Mingbo JIA,Liyan ZHAO. Research progress in effects of hypoxia-inducible factors on cell migration and invasion during epithelial-mesenchymal transition in glioma cells[J].Journal of Jilin University(Medicine Edition), 2025, 51(4): 1145-1154.

References 67

[1]	TAN H X， CAO Z B， HE T T， et al. TGFβ1 is essential for MSCs-CAFs differentiation and promotes HCT116 cells migration and invasion via JAK/STAT3 signaling［J］. Onco Targets Ther， 2019， 12： 5323-5334.
[2]	YIN J H， WANG L， WANG Y， et al. Curcumin reverses oxaliplatin resistance in human colorectal cancer via regulation of TGF-β/Smad2/3 signaling pathway［J］. Onco Targets Ther， 2019， 12： 3893-3903.
[3]	ZHU L H， CHEN W， LI G Q， et al. Upregulated RACK1 attenuates gastric cancer cell growth and epithelial-mesenchymal transition via suppressing Wnt/β-catenin signaling［J］. Onco Targets Ther， 2019， 12： 4795-4805.
[4]	MAHASE S， RATTENNI R N， WESSELING P， et al. Hypoxia-mediated mechanisms associated with antiangiogenic treatment resistance in glioblastomas［J］. Am J Pathol， 2017， 187（5）： 940-953.
[5]	KUSAMA K， FUKUSHIMA Y， YOSHIDA K， et al. Endometrial epithelial-mesenchymal transition （EMT） by menstruation-related inflammatory factors during hypoxia［J］. Mol Hum Reprod， 2021， 27（6）： gaab036.
[6]	LIN J C， TSAI J T， CHAO T Y， et al. The STAT3/slug axis enhances radiation-induced tumor invasion and cancer stem-like properties in radioresistant glioblastoma［J］. Cancers， 2018， 10（12）： 512.
[7]	KAHLERT U D， MACIACZYK D， DOOSTKAM S， et al. Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition［J］. Cancer Lett， 2012， 325（1）： 42-53.
[8]	KONG D J， WANG Z W， SARKAR S H， et al. Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells［J］. Stem Cells， 2008， 26（6）： 1425-1435.
[9]	LU Z M， GHOSH S， WANG Z Y， et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin， increased transcriptional activity of beta-catenin， and enhanced tumor cell invasion［J］. Cancer Cell， 2003， 4（6）： 499-515.
[10]	ZHANG J， CAI H Q， SUN L X， et al. LGR5， a novel functional glioma stem cell marker， promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients［J］. J Exp Clin Cancer Res， 2018， 37（1）： 225.
[11]	ZHAO L， LI X Q， SU J， et al. STAT1 determines aggressiveness of glioblastoma both in vivo and in vitro through Wnt/β-catenin signalling pathway［J］. Cell Biochem Funct， 2020， 38（5）： 630-641.
[12]	CHI D P， ZHANG W， JIA Y L， et al. Spalt-like transcription factor 1 （SALL1） gene expression inhibits cell proliferation and cell migration of human glioma cells through the Wnt/β-catenin signaling pathway［J］. Med Sci Monit Basic Res， 2019， 25： 128-138.
[13]	LIU Z J， LIU H L， ZHOU H C， et al. TIPE2 inhibits hypoxia-induced Wnt/β-catenin pathway activation and EMT in glioma cells［J］. Oncol Res， 2016， 24（4）： 255-261.
[14]	LIANG Y K， VOSHART D， PARIDAEN J T M L， et al. CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling［J］. Cell Mol Life Sci， 2022， 79（8）： 398.
[15]	PU B， ZHANG X， YAN T F， et al. Mical2 promotes proliferation and migration of glioblastoma cells through TGF-β/p-Smad2/EMT-Like signaling pathway［J］. Front Oncol， 2021， 11： 735180.
[16]	SUN E Y， LI Z， CAI H H， et al. HOXC6 regulates the epithelial-mesenchymal transition through the TGF-β/smad signaling pathway and predicts a poor prognosis in glioblastoma［J］. J Oncol， 2022， 2022： 8016102.
[17]	GAO Y， ZHENG H， LI L D， et al. KIF3C promotes proliferation， migration， and invasion of glioma cells by activating the PI3K/AKT pathway and inducing EMT［J］. Biomed Res Int， 2020， 2020： 6349312.
[18]	GAO K， JI Z W， SHE K， et al. Long non-coding RNA ZFAS1 is an unfavourable prognostic factor and promotes glioma cell progression by activation of the Notch signaling pathway［J］. Biomedecine Pharmacother， 2017， 87： 555-560.
[19]	WANG Y R， SONG W， KAN P C， et al. Overexpression of Epsin3 enhances migration and invasion of glioma cells by inducing epithelial-mesenchymal transition［J］. Oncol Rep， 2018， 40（5）： 3049-3059.
[20]	LEI J J， MA J G， MA Q Y， et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner［J］. Mol Cancer， 2013， 12： 66.
[21]	SHI J， CHEN J， SERRADJI N， et al. PMS1077 sensitizes TNF-α induced apoptosis in human prostate cancer cells by blocking NF-κB signaling pathway［J］. PLoS One， 2013， 8（4）： e61132.
[22]	ZHANG L， ZHANG W， LI Y， et al. SHP-2-upregulated ZEB1 is important for PDGFRα-driven glioma epithelial-mesenchymal transition and invasion in mice and humans［J］. Oncogene， 2016， 35（43）： 5641-5652.
[23]	LV F， DU Q， LI L， et al. Eriodictyol inhibits glioblastoma migration and invasion by reversing EMT via downregulation of the P38 MAPK/GSK-3β/ZEB1 pathway［J］. Eur J Pharmacol， 2021， 900： 174069.
[24]	CHEN B， LI X L， WU L H， et al. Quercetin suppresses human glioblastoma migration and invasion via GSK3β/β-catenin/ZEB1 signaling pathway ［J］. Front Pharmacol， 2022， 13： 963614.
[25]	YANG W， WU P F， MA J X， et al. Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3β/β-catenin/twist pathway［J］. Cell Death Dis， 2019， 10（3）： 208.
[26]	YANG L Q， LIN C Y， WANG L， et al. Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications［J］. Exp Cell Res， 2012， 318（19）： 2417-2426.
[27]	JOCHMANOVÁ I， ZELINKA T， WIDIMSKÝ J Jr， et al. HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors［J］. Physiol Res， 2014， 63（）： S251-S262.
[28]	GORT E H， GROOT A J， VAN DER WALL E， et al. Hypoxic regulation of metastasis via hypoxia-inducible factors［J］. Curr Mol Med， 2008， 8（1）： 60-67.
[29]	SEMENZA G L. Oxygen sensing， hypoxia-inducible factors， and disease pathophysiology［J］. Annu Rev Pathol， 2014， 9： 47-71.
[30]	PERSANO L， PISTOLLATO F， RAMPAZZO E， et al. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression［J］. Cell Death Dis， 2012， 3（10）： e412.
[31]	MALEKAN M， EBRAHIMZADEH M A， SHEIDA F. The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma［J］. Biomed Pharmacother， 2021， 141： 111873.
[32]	LU N， PIAO M H， FENG C S， et al. Isoflurane promotes epithelial-to-mesenchymal transition and metastasis of bladder cancer cells through HIF-1α-β-catenin/ Notch1 pathways［J］. Life Sci， 2020， 258： 118154.
[33]	WEI M， MA R， HUANG S L， et al. Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia［J］. J Cell Physiol， 2019， 234（10）： 17392-17404.
[34]	HUANG W Y， DING X P， YE H B， et al. Hypoxia enhances the migration and invasion of human glioblastoma U87 cells through PI3K/Akt/mTOR/HIF-1α pathway［J］. Neuroreport， 2018， 29（18）： 1578-1585.
[35]	XIA P， XU X Y. PI3K/Akt/mTOR signaling pathway in cancer stem cells： from basic research to clinical application［J］. Am J Cancer Res， 2015， 5（5）： 1602-1609.
[36]	LIN Y H， GUO L. GLI1 is involved in HIF-1α-induced migration， invasion， and epithelial-mesenchymal transition in glioma cells［J］. Folia Histochem Cytobiol， 2022， 60（2）： 156-166.
[37]	WANG T C， LUO S J， LIN C L， et al. Modulation of p75 neurotrophin receptor under hypoxic conditions induces migration and invasion of C6 glioma cells［J］. Clin Exp Metastasis， 2015， 32（1）： 73-81.
[38]	TONG B， PANTAZOPOULOU V， JOHANSSON E， et al. The p75 neurotrophin receptor enhances HIF-dependent signaling in glioma［J］. Exp Cell Res， 2018， 371（1）： 122-129.
[39]	KIM K Y， PERKINS G A， SHIM M S， et al. DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma［J］. Cell Death Dis， 2015， 6（8）： e1839.
[40]	ZHANG B， CHEN Y， SHI X L， et al. Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma［J］. Cell Mol Life Sci， 2021， 78（1）： 195-206.
[41]	ZHANG B， CHEN Y， BAO L， et al. GPT2 is induced by hypoxia-inducible factor （HIF）-2 and promotes glioblastoma growth［J］. Cells， 2022， 11（16）： 2597.
[42]	WANG Q， ZHANG C， ZHU J L， et al. Crucial role of RLIP76 in promoting glycolysis and tumorigenesis by stabilization of HIF-1α in glioma cells under hypoxia［J］. Mol Neurobiol， 2022， 59（11）： 6724-6739.
[43]	ZHANG G， TAO X， JI B W， et al. Hypoxia-driven M2-polarized macrophages facilitate cancer aggressiveness and temozolomide resistance in glioblastoma［J］. Oxid Med Cell Longev， 2022， 2022： 1614336.
[44]	ZHANG P C， LIU X， LI M M， et al. AT-533， a novel Hsp90 inhibitor， inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo ［J］. Biochem Pharmacol， 2020， 172： 113771.
[45]	SRIVASTAVA C， IRSHAD K， DIKSHIT B， et al. FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma［J］. Int J Cancer， 2018， 142（4）： 805-812.
[46]	ZHANG S Y， WANG W W， LIU G X， et al. Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis［J］. Biomedecine Pharmacother， 2017， 95： 711-720.
[47]	DEPNER C， BUTTEL HZUM， BÖĞÜRCÜ N， et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance［J］. Nat Commun， 2016， 7： 12329.
[48]	LIU H， CHEN C J， ZENG J H， et al. MicroRNA-210-3p is transcriptionally upregulated by hypoxia induction and thus promoting EMT and chemoresistance in glioma cells［J］. PLoS One， 2021， 16（7）： e0253522.
[49]	SONG Y， ZHENG S H， WANG J Z， et al. Hypoxia-induced PLOD2 promotes proliferation， migration and invasion via PI3K/Akt signaling in glioma ［J］. Oncotarget， 2017， 8（26）： 41947-41962.
[50]	KAR R， JHA N K， JHA S K， et al. A “NOTCH” deeper into the epithelial-to-mesenchymal transition （EMT） program in breast cancer［J］. Genes， 2019， 10（12）： 961.
[51]	DE CRAENE B， BERX G. Regulatory networks defining EMT during cancer initiation and progression［J］. Nat Rev Cancer， 2013， 13（2）： 97-110.
[52]	LOH C Y， CHAI J Y， TANG T F， et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition： signaling， therapeutic implications， and challenges［J］. Cells， 2019， 8（10）： 1118.
[53]	LIU T J， ZHAO X L， ZHENG X， et al. The EMT transcription factor， Twist1， as a novel therapeutic target for pulmonary sarcomatoid carcinomas［J］. Int J Oncol， 2020， 56（3）： 750-760.
[54]	TRAN D D， CORSA C A， BISWAS H， et al. Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence［J］. Mol Cancer Res， 2011， 9（12）： 1644-1657.
[55]	ZHANG W J， SHI X P， PENG Y， et al. HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer［J］. PLoS One， 2015， 10（6）： e0129603.
[56]	JOSEPH J V， CONROY S， PAVLOV K， et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis［J］. Cancer Lett， 2015， 359（1）： 107-116.
[57]	CHEN Z M， MOU L， PAN Y H， et al. CXCL8 promotes glioma progression by activating the JAK/STAT1/HIF-1α/snail signaling axis［J］. Onco Targets Ther， 2019， 12： 8125-8138.
[58]	NOPPARAT J， ZHANG J， LU J P， et al. δ-Catenin， a Wnt/β-catenin modulator， reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming［J］. Oncogene， 2015， 34（12）： 1542-1552.
[59]	LIU H， YIN J， WANG H S， et al. FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells［J］. Cell Signal， 2015， 27（3）： 510-518.
[60]	TIAN Q， XUE Y， ZHENG W， et al. Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling［J］. Int J Oncol， 2015， 47（2）： 728-738.
[61]	QIANG L， WU T， ZHANG H W， et al. HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway［J］. Cell Death Differ， 2012， 19（2）： 284-294.
[62]	SU X S， YANG Y H， GUO C F， et al. NOX4-derived ROS mediates TGF-β1-induced metabolic reprogramming during epithelial-mesenchymal transition through the PI3K/AKT/HIF-1α pathway in glioblastoma［J］. Oxid Med Cell Longev， 2021， 2021： 5549047.
[63]	ONISHI H， KAI M， ODATE S， et al. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer［J］. Cancer Sci， 2011， 102（6）： 1144-1150.
[64]	BHURIA V， XING J， SCHOLTA T， et al. Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness， epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma［J］. Exp Cell Res， 2019， 385（2）： 111671.
[65]	LIU J H， GAO L， ZHAN N， et al. Hypoxia induced ferritin light chain （FTL） promoted epithelia mesenchymal transition and chemoresistance of glioma［J］. J Exp Clin Cancer Res， 2020， 39（1）： 137.
[66]	ZHANG L， CAO Y Y， GUO X X， et al. Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma［J］. J Zhejiang Univ Sci B， 2023， 24（1）： 32-49.
[67]	QIU W J， SONG S B， CHEN W， et al. Hypoxia-induced EPHB2 promotes invasive potential of glioblastoma［J］. Int J Clin Exp Pathol， 2019， 12（2）： 539-548.

Research progress in effects of hypoxia-inducible factors on cell migration and invasion during epithelial-mesenchymal transition in glioma cells

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

References 67

Related Articles 15

Metrics

Comments

Recommended 10

[1]	Xiao ZHOU,Haitao DAI,Yunshan DING,Linjie ZHANG,Nan WU. Network pharmacology analysis and in vitro experimental validation of anticancer effect of grape seed proanthocyanidins against oral squamous cell carcinoma [J]. Journal of Jilin University(Medicine Edition), 2026, 52(3): 651-662.
[2]	Qiaotong REN,Weihua WU,Xingxiang WANG,Shichao WANG,Yipeng CHENG,Chun LI. Effect of interleukin-17 recepter B gene silencing on proliferation, invasion and apoptosis of lung adenocarcinoma A549 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2026, 52(3): 738-745.
[3]	Lina ZHANG,Zhesi MENG,Long BA,Jun MENG. Research progress in relationship between cell division cycle protein 6 and occurrence and development of tumor [J]. Journal of Jilin University(Medicine Edition), 2026, 52(3): 847-853.
[4]	Li ZHAI,Meng CHEN,Jianbo LUO,Aili ZHANG,Liangxiao WANG,Ying WEI,Xi ZHANG. Targeting relationship between miR-214-3p and EZH2 and its effects on proliferation， invasion， and apoptosis of ovarian cancer SKOV3 cells [J]. Journal of Jilin University(Medicine Edition), 2026, 52(2): 460-468.
[5]	Hong LI,Panpan YU,Zouyu ZHAO,Chongfeng SUN,Hui QIAO,Ping YANG. Expression of GSTO1 in ovarian cancer tissue and effect of N-glycosylation site mutations on biological behaviors of epithelial ovarian cancer cells [J]. Journal of Jilin University(Medicine Edition), 2026, 52(2): 469-482.
[6]	Yunshan DING,Haitao DAI,Min CHEN,Xiaohui HAO,Xiao ZHOU,Nan WU. Effect of silencing TRPV2 gene and cannabidiol on biological behaviors of oral squamous cell carcinoma CAL-27 cells [J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 143-151.
[7]	Dongxin JIANG, Yunqian LI. Research progress in clinical diagnosis and treatment of oligodendroglioma [J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 272-280.
[8]	Sifan FENG,Yunfeng LI,Jiaying WANG,Fubin MA,Yan WANG. Effects of heme-binding protein 1 gene knockdown on proliferation, migration, and inflammatory response of microglia BV2 and their mechanisms [J]. Journal of Jilin University(Medicine Edition), 2025, 51(6): 1532-1541.
[9]	Pingsheng ZHU,Sitang GE,Lugen ZUO,Deli CHEN,Yangyang ZHANG. Effect of miR-325-3p targeting PRELID1 gene in regulation of EMT pathway on invasion and migration of colon cancer cells and their mechanisms [J]. Journal of Jilin University(Medicine Edition), 2025, 51(5): 1185-1193.
[10]	Weigao SHEN,Yuqi LIU,Jun ZHANG,Jiayu LIN,Hang CUI,Yanbo LIU. Bioinformatics analysis on effect of interleukin-33 on occurrence and development of malignant brain glioma and its experimental validation [J]. Journal of Jilin University(Medicine Edition), 2025, 51(5): 1318-1332.
[11]	Wenxuan LI,Minru ZONG. Research progress in role of migration of Schwann cells in repairment of peripheral nerve injury [J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 1137-1144.
[12]	Yixuan GAO,Peng WANG,Silong ZHANG,Ruijuan GAO,Yingfang MA,Keke ZHANG,Dan FENG,Zongqi HUANG,Ketao MA,Li LI,Junqiang SI. Inhibitory effect of safranal on proliferation, migration and phenotypic transformation of vascular smooth muscle cells of rats induced by high glucose in vitro [J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 948-957.
[13]	Hongli LI,Mengyao WANG,Yangyang LIU,Hui ZHANG,Li LI. Effect of KHSRP on biological behavior of colorectal cancer cells through activation of JAK/STAT signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 996-1006.
[14]	Xingxiang WANG,Ying ZHAO,Qiaotong REN,Hefei WANG,Gang PU,Chun LI. Promotive effect of M2 macrophages on epithelial-mesenchymal transition and cisplatin resistance in non-small cell lung cancer A549 cells by regulating NF-κB signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2025, 51(3): 642-652.
[15]	Donghui LIU,Yunzhe CI,Chunyan WANG,Wenyi MA. Effect of miR-199a-5p on expression of Caveolin-1, cell migration and apoptosis in glioma U251 cells [J]. Journal of Jilin University(Medicine Edition), 2025, 51(3): 663-671.