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2000
Volume 26, Issue 7
  • ISSN: 1389-2037
  • E-ISSN: 1875-5550

Abstract

Background

Glioblastoma is a common primary malignant intracranial tumor in adults associated with high disability and mortality. Despite the use of traditional surgical methods, postoperative radiotherapy, and targeted therapies, the median survival for glioma patients remains disappointingly brief. As a result, there is an urgent need to explore new targets and develop novel targeted drugs to potentially improve patient survival. Notably, CLIC1 expression is upregulated in tumors and correlated to tumor aggressiveness, metastasis, and poor prognosis. Nonetheless, its potential role in gliomas remains largely unclear.

Objective

This study aimed to investigate the bioinformatics characteristics and clinicopathological features of CLIC1, including WHO classification and OS.

Methods

Immunohistochemistry and western blot analysis were carried out to detect the expression of CLIC1 in glioma tissues. Moreover, CCK8, plate clone formation assay, and EdU proliferation assay were carried out for cell proliferation ability. Transwell and scratch assay were performed for cell invasion and migration. Western blotting was also conducted to verify the relationship between CLIC1 and EMT and ERK1/2 signaling pathway. The effect of the knockdown of CLIC1 on tumor growth capacity was assessed in an intracranial xenograft model.

Results

CLIC1 was found to be associated with poor prognosis in glioma patients, and experiments demonstrated that CLIC1 promoted GBM cell proliferation, invasion, and migration. In addition, CLIC1 positively regulated ERK1/2 signaling to promote the EMT process in GBM cells. experiments showed that CLIC1 could affect intracranial tumor progression in mice.

Conclusion

In summary, these findings expand our knowledge of CLIC1, confirming its oncogenic role and laying the groundwork for future development of pharmacological agents targeting this gene.

© 2025 Bentham Science Publishers
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2025-09-03

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References

  1. OstromQ.T. PatilN. CioffiG. WaiteK. KruchkoC. Barnholtz-SloanJ.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017.Neuro-oncol.20202212Suppl. 1iv1iv9610.1093/neuonc/noaa20033123732
     [Google Scholar]
  2. WellerM. van den BentM. PreusserM. Le RhunE. TonnJ.C. MinnitiG. BendszusM. BalanaC. ChinotO. DirvenL. FrenchP. HegiM.E. JakolaA.S. PlattenM. RothP. RudàR. ShortS. SmitsM. TaphoornM.J.B. von DeimlingA. WestphalM. SoffiettiR. ReifenbergerG. WickW. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.Nat. Rev. Clin. Oncol.202118317018610.1038/s41571‑020‑00447‑z33293629
     [Google Scholar]
  3. WenP.Y. KesariS. Malignant gliomas in adults.N. Engl. J. Med.2008359549250710.1056/NEJMra070812618669428
     [Google Scholar]
  4. RaghuA.L.B. ChenJ.A. ValdesP.A. EssayedW.I. ClausE. ArnaoutO. SmithT.R. ChioccaE.A. PeruzziP.P. BernstockJ.D. Cerebellar high-grade glioma: A translationally oriented review of the literature.Cancers (Basel)202215117410.3390/cancers1501017436612169
     [Google Scholar]
  5. ZhengZ. SongY. Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers.BMC Bioinformatics20232415110.1186/s12859‑023‑05180‑936792990
     [Google Scholar]
  6. MorettiI.F. LerarioA.M. SolaP.R. Macedo-da-SilvaJ. da Silva BaptistaM. PalmisanoG. Oba-ShinjoS.M. MarieS.K.N. GBM cells exhibit susceptibility to metformin treatment according to TLR4 pathway activation and metabolic and antioxidant status.Cancers (Basel)202315358710.3390/cancers1503058736765551
     [Google Scholar]
  7. PanL. MengF. WangW. WangX. ShenH. BaoP. KangJ. KongD. Nintedanib in an elderly non-small-cell lung cancer patient with severe steroid-refractory checkpoint inhibitor-related pneumonitis: A case report and literature review.Front. Immunol.202313107261210.3389/fimmu.2022.107261236703957
     [Google Scholar]
  8. WangM. ZhangC. ZhengQ. MaZ. QiM. DiG. LingS. XuH. QiB. YaoC. XiaH. JiangX. RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways.Int. J. Biol. Sci.202218394295510.7150/ijbs.6565335173528
     [Google Scholar]
  9. MehtaS. FiorelliR. BaoX. Pennington-KrygierC. DerogatisA. KimS. YooW. LiJ. SanaiN. A phase 0 trial of ceritinib in patients with brain metastases and recurrent glioblastoma.Clin. Cancer Res.202228228929710.1158/1078‑0432.CCR‑21‑109634702773
     [Google Scholar]
  10. ZhaoM. van StratenD. BroekmanM.L.D. PréatV. SchiffelersR.M. Nanocarrier-based drug combination therapy for glioblastoma.Theranostics20201031355137210.7150/thno.3814731938069
     [Google Scholar]
  11. MoralesD.E. MousaS. Intranasal delivery in glioblastoma treatment: Prospective molecular treatment modalities.Heliyon202285e0951710.1016/j.heliyon.2022.e0951735647354
     [Google Scholar]
  12. SchalperK.A. Rodriguez-RuizM.E. Diez-ValleR. López-JaneiroA. PorciunculaA. IdoateM.A. InogésS. de AndreaC. López-Diaz de CerioA. TejadaS. BerraondoP. Villarroel-EspindolaF. ChoiJ. GúrpideA. GiraldezM. GoicoecheaI. Gallego Perez-LarrayaJ. SanmamedM.F. Perez-GraciaJ.L. MeleroI. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma.Nat. Med.201925347047610.1038/s41591‑018‑0339‑530742120
     [Google Scholar]
  13. ShuC. LiQ. Current advances in PD-1/PD-L1 axis-related tumour-infiltrating immune cells and therapeutic regimens in glioblastoma.Crit. Rev. Oncol. Hematol.202015110296510.1016/j.critrevonc.2020.10296532442903
     [Google Scholar]
  14. RominiyiO. VanderlindenA. ClentonS.J. BridgewaterC. Al-TamimiY. CollisS.J. Tumour treating fields therapy for glioblastoma: Current advances and future directions.Br. J. Cancer2021124469770910.1038/s41416‑020‑01136‑533144698
     [Google Scholar]
  15. PantA. LimM. CAR-T therapy in GBM: Current challenges and avenues for improvement.Cancers (Basel)2023154124910.3390/cancers1504124936831591
     [Google Scholar]
  16. ZannikouM. DuffyJ.T. LevineR.N. SeblaniM. LiuQ. PresserA. ArrietaV.A. ChenC.J. SonabendA.M. HorbinskiC.M. Lee-ChangC. MiskaJ. LesniakM.S. GottschalkS. BalyasnikovaI.V. IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.J. Immunother. Cancer2023112e00623910.1136/jitc‑2022‑00623936759014
     [Google Scholar]
  17. LittlerD.R. HarropS.J. GoodchildS.C. PhangJ.M. MynottA.V. JiangL. ValenzuelaS.M. MazzantiM. BrownL.J. BreitS.N. CurmiP.M.G. The enigma of the CLIC proteins: Ion channels, redox proteins, enzymes, scaffolding proteins?FEBS Lett.2010584102093210110.1016/j.febslet.2010.01.02720085760
     [Google Scholar]
  18. LuD. LeY. DingJ. DouX. MaoW. ZhuJ. CLIC1 inhibition protects against cellular senescence and endothelial dysfunction via the Nrf2/HO-1 pathway.Cell Biochem. Biophys.202179223925210.1007/s12013‑020‑00959‑633432550
     [Google Scholar]
  19. GengH. FengC. SunZ. FanX. XieY. GuJ. FanL. LiuG. LiC. ThorneR.F. ZhangX.D. LiX. LiuX. Chloride intracellular channel 1 promotes esophageal squamous cell carcinoma proliferation via mTOR signalling.Transl. Oncol.20232710156010.1016/j.tranon.2022.10156036252281
     [Google Scholar]
  20. PengJ.M. LinS.H. YuM.C. HsiehS.Y. CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis.J. Clin. Invest.20211311e13352510.1172/JCI13352533079727
     [Google Scholar]
  21. BarbieriF. BosioA.G. PattarozziA. TonelliM. BajettoA. VerduciI. CianciF. CannavaleG. PalloniL.M.G. FrancesconiV. ThellungS. FiaschiP. MazzettiS. SchenoneS. BalboniB. GirottoS. MalatestaP. DagaA. ZonaG. MazzantiM. FlorioT. Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives.J. Exp. Clin. Cancer Res.20224115310.1186/s13046‑021‑02213‑035135603
     [Google Scholar]
  22. ZhangS. WangX.M. YinZ.Y. ZhaoW.X. ZhouJ.Y. ZhaoB.X. LiuP.G. Chloride intracellular channel 1 is overexpression in hepatic tumor and correlates with a poor prognosis.Acta Pathol. Microbiol. Scand. Suppl.2013121111047105310.1111/apm.1209323593969
     [Google Scholar]
  23. ChangY.H. WuC.C. ChangK.P. YuJ.S. ChangY.C. LiaoP.C. Cell secretome analysis using hollow fiber culture system leads to the discovery of CLIC1 protein as a novel plasma marker for nasopharyngeal carcinoma.J. Proteome Res.20098125465547410.1021/pr900454e19845400
     [Google Scholar]
  24. NesiuA. CimpeanA.M. CeausuR.A. AdileA. IoiartI. PortaC. MazzantiM. CamerotaT.C. RaicaM. Intracellular chloride ion channel protein-1 expression in clear cell renal cell carcinoma.Cancer Genomics Proteomics201916429930710.21873/cgp.2013531243111
     [Google Scholar]
  25. GuoQ. JinY. ChenX. YeX. ShenX. LinM. ZengC. ZhouT. ZhangJ. NF-κB in biology and targeted therapy: New insights and translational implications.Signal Transduct. Target. Ther.2024915310.1038/s41392‑024‑01757‑938433280
     [Google Scholar]
  26. BoultonT.G. YancopoulosG.D. GregoryJ.S. SlaughterC. MoomawC. HsuJ. CobbM.H. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control.Science19902494964646710.1126/science.21642592164259
     [Google Scholar]
  27. KongX. AnP. XuJ. LiuW. LinF. YangY. A-kinase anchor protein 95 is involved in ERK1/2–Elk-1 signal transduction in colon cancer.Anal. Cell. Pathol. (Amst.)202320231710.1155/2023/824264636691407
     [Google Scholar]
  28. DaneshmandiS. YanQ. ChoiJ.E. KatsutaE. MacDonaldC.R. GoruganthuM. RobertsN. RepaskyE.A. SinghP.K. AttwoodK. WangJ. LandesmanY. McCarthyP.L. MohammadpourH. Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.Cell. Mol. Immunol.202421887389110.1038/s41423‑024‑01187‑138902348
     [Google Scholar]
  29. ZhangL. ChenX. YaoS. ZhengL. YangX. WangY. LiX. WuE. TuoB. Intracellular chloride channel 1 and tumor.Am. J. Cancer Res.20231383300331437693147
     [Google Scholar]
  30. WangP. ZengY. LiuT. ZhangC. YuP.W. HaoY.X. LuoH.X. LiuG. Chloride intracellular channel 1 regulates colon cancer cell migration and invasion through ROS/ERK pathway.World J. Gastroenterol.20142082071207810.3748/wjg.v20.i8.207124587680
     [Google Scholar]
  31. LiY. SunT. ChenZ. ShaoY. HuangY. ZhouY. Characterization of a new human astrocytoma cell line SHG140: cell proliferation, cell phenotype, karyotype, STR markers and tumorigenicity analysis.J. Cancer202112237137810.7150/jca.4080233391433
     [Google Scholar]
  32. ZhangK. WuY. ChenG. WangH. LiuY. ZhouY. Heat shock protein 27 deficiency promotes ferrous ion absorption and enhances acyl-Coenzyme A synthetase long-chain family member 4 stability to promote glioblastoma cell ferroptosis.Cancer Cell Int.2023231510.1186/s12935‑023‑02848‑336639654
     [Google Scholar]
  33. LiZ. DuL. LiC. WuW. Human chorionic gonadotropin β induces cell motility via ERK1/2 and MMP-2 activation in human glioblastoma U87MG cells.J. Neurooncol.2013111323724410.1007/s11060‑012‑1017‑y23232806
     [Google Scholar]
  34. AgnihotriS. BurrellK. BuczkowiczP. RemkeM. GolbournB. ChornenkyyY. GajadharA. FernandezN.A. ClarkeI.D. BarszczykM.S. PajovicS. TernamianC. HeadR. SabhaN. SobolR.W. TaylorM.D. RutkaJ.T. JonesC. DirksP.B. ZadehG. HawkinsC. ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.Cancer Discov.20144101198121310.1158/2159‑8290.CD‑14‑015725100205
     [Google Scholar]
  35. LiT. YiL. HaiL. MaH. TaoZ. ZhangC. AbeysekeraI.R. ZhaoK. YangY. WangW. LiuB. YuS. TongL. LiuP. ZhuM. RenB. LinY. ZhangK. ChengC. HuangY. YangX. The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion.Cell Death Dis.20189329210.1038/s41419‑017‑0253‑729463791
     [Google Scholar]
  36. LattierJ.M. DeA. ChenZ. MoralesJ.E. LangF.F. HuseJ.T. McCartyJ.H. Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) promotes glioblastoma cell invasion in the brain microenvironment.Oncogene202039507253726410.1038/s41388‑020‑01503‑933040087
     [Google Scholar]
  37. LeeY.J. JungJ.H. ChangD.Y. KimM.G. BashyalN. HwangW.S. WooH.G. PaekS.H. Suh-KimH. KimS.S. THOC2 expression and its impact on 5-fluorouracil resistance in glioblastoma multiforme.Am. J. Cancer Res.20231362410242537424800
     [Google Scholar]
  38. GurskiL.A. KnowlesL.M. BasseP.H. MaranchieJ.K. WatkinsS.C. PilchJ. Relocation of CLIC1 promotes tumor cell invasion and colonization of fibrin.Mol. Cancer Res.201513227328010.1158/1541‑7786.MCR‑14‑024925205595
     [Google Scholar]
  39. LiB. MaoY. WangZ. ChenY. WangY. ZhaiC. ShiB. LiuS. LiuJ. ChenJ. CLIC1 promotes the progression of gastric cancer by regulating the MAPK/AKT pathways.Cell. Physiol. Biochem.201846390792410.1159/00048882229669336
     [Google Scholar]
  40. TianY. GuanY. JiaY. MengQ. YangJ. Chloride intracellular channel 1 regulates prostate cancer cell proliferation and migration through the MAPK/ERK pathway.Cancer Biother. Radiopharm.201429833934410.1089/cbr.2014.166625279971
     [Google Scholar]
  41. ShiH. SunL. ZhengD. XuG. ShaoG. Long NoncodingR.N.A. Long noncoding RNA HLA complex group 18 improves the cell proliferation of myocardial fibroblasts by regulating the Hsa-microRNA-133a/epidermal growth factor receptor axis.Evid. Based Complement. Alternat. Med.202220221810.1155/2022/266823935958914
     [Google Scholar]
  42. PengT. GuoY. GanZ. LingY. XiongJ. LiangX. CuiJ. Nerve Growth Factor (NGF) encourages the neuroinvasive potential of pancreatic cancer cells by activating the warburg effect and promoting tumor derived exosomal miRNA-21 expression.Oxid. Med. Cell. Longev.2022202211910.1155/2022/844509336285300
     [Google Scholar]
  43. ValdezL. ChengB. GonzalezD. RodriguezR. CampanoP. TsinA. FangX. Combined treatment with niclosamide and camptothecin enhances anticancer effect in U87 MG human glioblastoma cells.Oncotarget202213164265810.18632/oncotarget.2822735548329
     [Google Scholar]
  44. HuangC. JacobsonK. SchallerM.D. MAP kinases and cell migration.J. Cell Sci.2004117204619462810.1242/jcs.0148115371522
     [Google Scholar]
  45. ChakrabortiS. MandalM. DasS. MandalA. ChakrabortiT. Regulation of matrix metalloproteinases: An overview.Mol. Cell. Biochem.20032531/226928510.1023/A:102602830319614619979
     [Google Scholar]
  46. BalmannoK. CookS.J. Tumour cell survival signalling by the ERK1/2 pathway.Cell Death Differ.200916336837710.1038/cdd.2008.14818846109
     [Google Scholar]
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Chloride Intracellular Channel 1 Enhances Glioblastoma Cell Migration and Epithelial-Mesenchymal Transition by Activating the ERK1/2 Signaling Pathway
Curr. Protein Pept. Sci. 26, 556 (2025); https://doi.org/10.2174/0113892037358160250205191300
/content/journals/cpps/10.2174/0113892037358160250205191300
/content/journals/cpps/10.2174/0113892037358160250205191300
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  • Article Type:     Research Article
Keyword(s): CLIC1; EMT; ERK1/2; GBM; migration; proliferation

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