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2000
Volume 32, Issue 13
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

microRNA (miRNA) levels are dysregulated in many cancers, suggesting that miRNA-based therapy may be effective. The molecular pathways of colorectal cancer (CRC) development are unknown.

Methods

Understanding miRNAs implicated in CRC formation may reveal new diagnostic and therapeutic targets. Angiogenesis is a key mechanism in tumor growth. CRC treatment may involve inhibiting angiogenesis, but existing drugs can cause negative effects. Tranexamic acid, an FDA-approved medication, may reduce the adverse effects of angiogenesis inhibitors. This work examined miRNAs implicated in CRC angiogenesis and how miR-16 and tranexamic acid may synergistically decrease CRC cell migration and angiogenesis. We identified miRNAs targeting CRC angiogenesis genes using bioinformatic databases. Proteins were docked with tranexamic acid utilizing the PyRx software. Quantitative Real-time PCR was used to analyze the effects of overexpressed miRNA and tranexamic acid on the expression of target genes. Scratch, transwell migration, and Chicken Chorioallantoic Membrane (CAM) assays were used to evaluate the effect of selected miRNA and tranexamic acid on the invasion and angiogenesis of CRC cells. studies identified hsa-miR-16-5p, -101-3p, and 34a-5p as possible CRC angiogenesis modulators.

Results

The study found that miR-16 and tranexamic acid influence the expression of VEGFA, ANGPT2, MMP9, and HIF1A. miR-16 and tranexamic acid influenced CRC cell movement in scratch tests and transwell migration assays. Furthermore, the CAM assay results demonstrated that miR-16 and tranexamic acid can alter angiogenesis in CRC.

Conclusion

These findings highlight the potential of miR-16 and tranexamic acid as combination therapeutic agents for CRC, with the ability to simultaneously target tumorigenesis and angiogenesis.

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References

  1. BaidounF. ElshiwyK. ElkeraieY. MerjanehZ. KhoudariG. SarminiM.T. GadM. Al-HusseiniM. SaadA. Colorectal cancer epidemiology: Recent trends and impact on outcomes.Curr. Drug Targets2021229998100910.2174/18735592MTEx9NTk2y33208072
    [Google Scholar]
  2. GuptaS. Screening for colorectal cancer.Hematol. Oncol. Clin. North Am.202236339341410.1016/j.hoc.2022.02.00135501176
    [Google Scholar]
  3. BrandiG. RicciA.D. RizzoA. ZanfiC. TavolariS. PalloniA. De LorenzoS. RavaioliM. CesconM. Is post-transplant chemotherapy feasible in liver transplantation for colorectal cancer liver metastases?Cancer Commun.202040946146410.1002/cac2.1207232762027
    [Google Scholar]
  4. RizzoA. NanniniM. NovelliM. Dalia RicciA. ScioscioV.D. PantaleoM.A. Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: A systematic review and meta-analysis.Ther. Adv. Med. Oncol.202012175883592093693210.1177/175883592093693232684988
    [Google Scholar]
  5. GuvenD.C. SahinT.K. ErulE. RizzoA. RicciA.D. AksoyS. YalcinS. The association between albumin levels and survival in patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.Front. Mol. Biosci.20229103912110.3389/fmolb.2022.103912136533070
    [Google Scholar]
  6. MollicaV. RizzoA. MarchettiA. TateoV. TassinariE. RoselliniM. MassafraR. SantoniM. MassariF. The impact of ECOG performance status on efficacy of immunotherapy and immune-based combinations in cancer patients: The MOUSEION-06 study.Clin. Exp. Med.20232385039504910.1007/s10238‑023‑01159‑137535194
    [Google Scholar]
  7. TangY. ZongS. ZengH. RuanX. YaoL. HanS. HouF. MicroRNAs and angiogenesis: A new era for the management of colorectal cancer.Cancer Cell Int.202121122110.1186/s12935‑021‑01920‑0
    [Google Scholar]
  8. KampoliK. FoukasP.G. NtavatzikosA. ArkadopoulosN. KoumarianouA. Interrogating the interplay of angiogenesis and immunity in metastatic colorectal cancer.World J. Methodol.2022121435310.5662/wjm.v12.i1.4335117981
    [Google Scholar]
  9. ItataniY. KawadaK. YamamotoT. SakaiY. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway.Int. J. Mol. Sci.2018194123210.3390/ijms1904123229670046
    [Google Scholar]
  10. KhanK. CunninghamD. ChauI. Targeting angiogenic pathways in colorectal cancer: Complexities, challenges and future directions.Curr. Drug Targets2016181567110.2174/138945011666615032523155525808652
    [Google Scholar]
  11. WuM. HuangQ. XieY. WuX. MaH. ZhangY. XiaY. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.J. Hematol. Oncol.20221512410.1186/s13045‑022‑01242‑235279217
    [Google Scholar]
  12. DarvishL. ToossiB.M.T. AzimianH. ShakeriM. DolatE. FirouzjaeiA.A. RezaieS. AmraeeA. BakhtiariA.S.H. The role of microRNA-induced apoptosis in diverse radioresistant cancers.Cell. Signal.202310411058010.1016/j.cellsig.2022.11058036581218
    [Google Scholar]
  13. FirouzjaeiA.A. SharifiK. KhazaeiM. YeganehM.S. BakhtiariA.S.H. Screening and introduction of key cell cycle microRNAs deregulated in colorectal cancer by integrated bioinformatics analysis.Chem. Biol. Drug Des.2023102113715210.1111/cbdd.1424237081586
    [Google Scholar]
  14. RupaimooleR. SlackF.J. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases.Nat. Rev. Drug Discov.201716320322210.1038/nrd.2016.24628209991
    [Google Scholar]
  15. AnneseT. TammaR. GiorgisD.M. RibattiD. microRNAs biogenesis, functions and role in tumor angiogenesis.Front. Oncol.20201058100710.3389/fonc.2020.58100733330058
    [Google Scholar]
  16. GoradelN.H. MohammadiN. Haghi-AminjanH. FarhoodB. NegahdariB. SahebkarA. Regulation of tumor angiogenesis by microRNAs: State of the art.J Cell Physiol201923421099111010.1002/jcp.27051
    [Google Scholar]
  17. VeraS.Y.M. MarchatL.A. RincónG.D. GarcíaR.E. De La VegaA.H. ZepedaE.R. CamarilloL.C. AngiomiRs: MicroRNAs driving angiogenesis in cancer (Review).Int. J. Mol. Med.201943265767010.3892/ijmm.2018.400330483765
    [Google Scholar]
  18. van BeijnumJ.R. GiovannettiE. PoelD. SliwinskaN.P. GriffioenA.W. miRNAs: Micro-managers of anticancer combination therapies.Angiogenesis201720226928510.1007/s10456‑017‑9545‑x28474282
    [Google Scholar]
  19. ColominaM.J. ContrerasL. GuilabertP. KooM. M NdezE. SabateA. Clinical use of tranexamic acid: Evidences and controversies.Brazil. J. Anesthesiol.202272679581210.1016/j.bjane.2021.08.02234626756
    [Google Scholar]
  20. FowlerH. LawJ. ThamS.M. GunaraviS.A. HoughtonN. CliffordR.E. FokM. BarkerJ.A. VimalachandranD. Impact on blood loss and transfusion rates following administration of tranexamic acid in major oncological abdominal and pelvic surgery: A systematic review and meta-analysis.J. Surg. Oncol.2022126360962110.1002/jso.2690035471705
    [Google Scholar]
  21. ShakerE. FayekE. ElrawasM. Evaluation of efficacy and safety of a single dose Tranexamic acid in reducing blood loss during colorectal cancer surgery. A randomised, placebo controlled, double-blinded study.Indian J. Anaesth.202367219420010.4103/ija.ija_576_2237091453
    [Google Scholar]
  22. ZhuJ.W. NiY.J. TongX.Y. GuoX. WuX.P. LuZ.F. Tranexamic acid inhibits angiogenesis and melanogenesis in vitro by targeting VEGF receptors.Int. J. Med. Sci.202017790391110.7150/ijms.4418832308543
    [Google Scholar]
  23. PaolacciS. PreconeV. AcquavivaF. ChiurazziP. FulcheriE. PinelliM. BuffelliF. MicheliniS. HerbstK.L. UnferV. BertelliM. Genetics of lipedema: New perspectives on genetic research and molecular diagnoses.Eur. Rev. Med. Pharmacol. Sci.201923135581559431298310
    [Google Scholar]
  24. LiberzonA. BirgerC. ThorvaldsdóttirH. GhandiM. MesirovJ.P. TamayoP. The Molecular Signatures Database (MSigDB) hallmark gene set collection.Cell Syst.20151641742510.1016/j.cels.2015.12.00426771021
    [Google Scholar]
  25. PiñeroJ. AnguitaR.J.M. PitarchS.J. RonzanoF. CentenoE. SanzF. FurlongL.I. The DisGeNET knowledge platform for disease genomics: 2019 update.Nucleic Acids Res.201948D1gkz102110.1093/nar/gkz102131680165
    [Google Scholar]
  26. EdgarR. DomrachevM. LashA.E. Gene expression omnibus: NCBI gene expression and hybridization array data repository.Nucleic Acids Res.200230120721010.1093/nar/30.1.20711752295
    [Google Scholar]
  27. FirouzjaeiA.A. BakhtiariA.S.H. TaftiA. SharifiK. AbadiM.H.J.N. RezaeiS. YeganehM.S. Impact of curcumin on ferroptosis-related genes in colorectal cancer: Insights from in-silico and in vitro studies.Cell Biochem. Funct.20234181488150210.1002/cbf.388938014635
    [Google Scholar]
  28. ChangL. ZhouG. SoufanO. XiaJ. miRNet 2.0: Network-based visual analytics for miRNA functional analysis and systems biology.Nucleic Acids Res.202048W1W244W25110.1093/nar/gkaa46732484539
    [Google Scholar]
  29. AbadiJ.F.M.H. KhorashadizadehM. JalianiZ.H. JamialahmadiK. BakhtiariA.S.H. miR-27 and miR-124 target AR coregulators in prostate cancer: Bioinformatics and in vitro analysis.2022549e1449710.1111/and.14497
    [Google Scholar]
  30. YeganehM.S. ParyanM. SamieeM.S. SoleimaniM. ArefianE. AzadmaneshK. MostafaviE. MahdianR. KarimipoorM. Development of a robust, low cost stem-loop real-time quantification PCR technique for miRNA expression analysis.Mol. Biol. Rep.20134053665367410.1007/s11033‑012‑2442‑x23307300
    [Google Scholar]
  31. GradaA. VinasO.M. CastrilloP.F. ObagiZ. FalangaV. Research techniques made simple: Analysis of collective cell migration using the wound healing assay.J. Invest. Dermatol.20171372e11e1610.1016/j.jid.2016.11.02028110712
    [Google Scholar]
  32. BaderA.G. BrownD. WinklerM. The promise of microRNA replacement therapy.Cancer Res.201070187027703010.1158/0008‑5472.CAN‑10‑201020807816
    [Google Scholar]
  33. ReddyK.B. MicroRNA (miRNA) in cancer.Cancer Cell Int.20151513810.1186/s12935‑015‑0185‑125960691
    [Google Scholar]
  34. HongL. HanY. YangJ. ZhangH. ZhaoQ. WuK. FanD. MicroRNAs in gastrointestinal cancer: Prognostic significance and potential role in chemoresistance.Expert Opin. Biol. Ther.20141481103111110.1517/14712598.2014.90778724707835
    [Google Scholar]
  35. HaibeY. KreidiehM. HajjE.H. KhalifehI. MukherjiD. TemrazS. ShamseddineA. Resistance mechanisms to anti-angiogenic therapies in cancer.Front. Oncol.20201022110.3389/fonc.2020.0022132175278
    [Google Scholar]
  36. Sanz-GarciaE. GrasselliJ. ArgilesG. ElezM.E. TaberneroJ. Current and advancing treatments for metastatic colorectal cancer.Expert Opin. Biol. Ther.20161619311010.1517/14712598.2016.110840526549053
    [Google Scholar]
  37. XiaoB. WangW. ZhangD. Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: A meta-analysis of 85 randomized controlled trials.OncoTargets Ther.2018115059507410.2147/OTT.S16615130174444
    [Google Scholar]
  38. CRASH-3 trial collaboratorsEffects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): A randomised, placebo-controlled trial.Lancet2019394102101713172310.1016/S0140‑6736(19)32233‑031623894
    [Google Scholar]
  39. ChenT. XiaoQ. WangX. WangZ. HuJ. ZhangZ. GongZ. ChenS. miR-16 regulates proliferation and invasion of lung cancer cells via the ERK/MAPK signaling pathway by targeted inhibition of MAPK kinase 1 (MEK1).J. Int. Med. Res.201947105194520410.1177/030006051985650531379227
    [Google Scholar]
  40. FardG.S. KhoshbakhtT. HussenB.M. AbdullahS.T. TaheriM. SamadianM. A review on the role of mir-16-5p in the carcinogenesis.Cancer Cell Int.202222134210.1186/s12935‑022‑02754‑036348403
    [Google Scholar]
  41. DwivediS.K.D. MustafiS.B. MangalaL.S. JiangD. PradeepS. AguayoR.C. LingH. IvanC. MukherjeeP. CalinG.A. BeresteinL.G. SoodA.K. BhattacharyaR. Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer.Oncotarget2016712150931510410.18632/oncotarget.761826918603
    [Google Scholar]
  42. TianR. WangJ. YanH. WuJ. XuQ. ZhanX. GuiZ. DingM. HeJ. Differential expression of miR16 in glioblastoma and glioblastoma stem cells: their correlation with proliferation, differentiation, metastasis and prognosis.Oncogene201736425861587310.1038/onc.2017.18228628119
    [Google Scholar]
  43. YoshimotoT. NiimiK. TakahashiE. Tranexamic acid and supportive measures to treat wasting marmoset syndrome.Comp. Med.201666646847328304250
    [Google Scholar]
  44. HiramotoK. YamateY. SugiyamaD. MatsudaK. IizukaY. YamaguchiT. Effect of tranexamic acid in improving the lifespan of naturally aging mice.Inflammopharmacology20192761319132310.1007/s10787‑019‑00616‑231236768
    [Google Scholar]
  45. HiramotoK. YamateY. SugiyamaD. MatsudaK. IizukaY. YamaguchiT. Tranexamic acid ameliorates nonmelanoma skin cancer induced by long-term ultraviolet a irradiation.Photochem. Photobiol.201995261261710.1111/php.1302530267577
    [Google Scholar]
  46. LuoW. HeD. ZhangJ. MaZ. ChenK. lvZ. FanC. YangL. LiY. ZhouZ. Knockdown of PPARδ induces VEGFA-mediated angiogenesis via interaction with ERO1A in human colorectal cancer.Front. Oncol.20211171389210.3389/fonc.2021.71389234712608
    [Google Scholar]
  47. XueG. YanH-L. ZhangY. HaoL-Q. ZhuX-T. MeiQ. SunS-H. c-Myc-mediated repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promotes tumor angiogenesis and metastasis by upregulating FGF2.Oncogene201534111393140610.1038/onc.2014.8224704828
    [Google Scholar]
  48. JaryM. HasanovaR. VienotA. AsgarovK. LoyonR. TiroleC. BouardA. OrillardE. KlajerE. KimS. ViotJ. ColleE. AdoteviO. Molecular description of ANGPT2 associated colorectal carcinoma.Int. J. Cancer202014772007201810.1002/ijc.32993
    [Google Scholar]
  49. ViallardC. LarrivéeB. Tumor angiogenesis and vascular normalization: Alternative therapeutic targets.Angiogenesis201720440942610.1007/s10456‑017‑9562‑928660302
    [Google Scholar]
  50. Frontiers Editorial OfficeRetraction: The design, characterizations, and tumor angiogenesis inhibition of a multi-epitope peptibody with bFGF/VEGFA.Front. Oncol.20211064469010.3389/fonc.2020.64469033585261
    [Google Scholar]
  51. VimalrajS. SubramanianR. SaravananS. ArumugamB. AnuradhaD. MicroRNA-432-5p regulates sprouting and intussusceptive angiogenesis in osteosarcoma microenvironment by targeting PDGFB.Lab. Invest.202110181011102510.1038/s41374‑021‑00589‑333846539
    [Google Scholar]
  52. MaT.H. GaoC.C. XieR. YangX.Z. DaiW.J. ZhangJ.L. YanW. WuS.N. Predictive values of FAP and HGF for tumor angiogenesis and metastasis in colorectal cancer.Neoplasma201764688088610.4149/neo_2017_60928895412
    [Google Scholar]
  53. QinS. YiM. JiaoD. LiA. WuK. Distinct roles of VEGFA and ANGPT2 in lung adenocarcinoma and squamous cell carcinoma.J. Cancer202011115316710.7150/jca.3469331892982
    [Google Scholar]
  54. BrunoA. BassaniB. D’UrsoD.G. PitakuI. CassinottiE. PelosiG. BoniL. DominioniL. NoonanD.M. MortaraL. AlbiniA. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.FASEB J.201832105365537710.1096/fj.201701103R29763380
    [Google Scholar]
  55. JinW. ChenF. WangK. SongY. FeiX. WuB. iR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-β signaling pathway.Biomed. Pharmacother.201810463764410.1016/j.biopha.2018.05.041
    [Google Scholar]
  56. FründtT. KrauseL. Diagnostic and prognostic value of miR-16, miR-146a, miR-192 and miR-221 in exosomes of hepatocellular carcinoma and liver cirrhosis patients.Cancers20211310248410.3390/cancers13102484
    [Google Scholar]
  57. WangZ. HuS. LiX. LiuZ. HanD. WangY. WeiL. ZhangG. WangX. MiR-16-5p suppresses breast cancer proliferation by targeting ANLN.BMC Cancer2021211118810.1186/s12885‑021‑08914‑1
    [Google Scholar]
  58. JiangX. WangZ. miR-16 targets SALL4 to repress the proliferation and migration of gastric cancer.Oncol. Lett.20181633005301210.3892/ol.2018.899730127890
    [Google Scholar]
  59. YouC. LiangH. SunW. LiJ. LiuY. FanQ. ZhangH. YueX. LiJ. ChenX. BaY. Deregulation of the miR-16-KRAS axis promotes colorectal cancer.Sci. Rep.2016613745910.1038/srep3745927857191
    [Google Scholar]
  60. CarmelietP. JainR.K. Angiogenesis in cancer and other diseases.Nature2000407680124925710.1038/3502522011001068
    [Google Scholar]
  61. FerraraN. KerbelR.S. Angiogenesis as a therapeutic target.Nature2005438707096797410.1038/nature0448316355214
    [Google Scholar]
  62. KaplanR.N. RibaR.D. ZacharoulisS. BramleyA.H. VincentL. CostaC. MacDonaldD.D. JinD.K. ShidoK. KernsS.A. ZhuZ. HicklinD. WuY. PortJ.L. AltorkiN. PortE.R. RuggeroD. ShmelkovS.V. JensenK.K. RafiiS. LydenD. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature2005438706982082710.1038/nature0418616341007
    [Google Scholar]
  63. BatchelorT.T. SorensenA.G. di TomasoE. ZhangW.T. DudaD.G. CohenK.S. KozakK.R. CahillD.P. ChenP.J. ZhuM. AncukiewiczM. MrugalaM.M. PlotkinS. DrappatzJ. LouisD.N. IvyP. ScaddenD.T. BennerT. LoefflerJ.S. WenP.Y. JainR.K. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.Cancer Cell2007111839510.1016/j.ccr.2006.11.02117222792
    [Google Scholar]
  64. WelshC.L. WelshM. VEGFA and tumour angiogenesis.J. Intern. Med.2013273211412710.1111/joim.1201923216836
    [Google Scholar]
  65. HurwitzH. FehrenbacherL. NovotnyW. CartwrightT. HainsworthJ. HeimW. BerlinJ. BaronA. GriffingS. HolmgrenE. FerraraN. FyfeG. RogersB. RossR. KabbinavarF. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N. Engl. J. Med.2004350232335234210.1056/NEJMoa03269115175435
    [Google Scholar]
  66. SonpavdeG. Bevacizumab in renal-cell cancer.N. Engl. J. Med.200334917167410.1056/NEJM20031023349171914573745
    [Google Scholar]
  67. CaoY. Emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis.Nat. Rev. Cancer20055973574310.1038/nrc169316079909
    [Google Scholar]
  68. CasanovasO. HicklinD.J. BergersG. HanahanD. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.Cancer Cell20058429930910.1016/j.ccr.2005.09.00516226705
    [Google Scholar]
  69. FanX. ZhouJ. BiX. LiangJ. LuS. YanX. LuoL. YinZ. L-theanine suppresses the metastasis of prostate cancer by downregulating MMP9 and Snail.J. Nutr. Biochem.20218910855610.1016/j.jnutbio.2020.10855633249185
    [Google Scholar]
  70. WalkiewiczK. KoziełP. BednarczykM. BłażelonisA. MazurekU. WierzgońM.M. Expression of migration-related genes in human colorectal cancer and activity of a disintegrin and metalloproteinase 17.BioMed Res. Int.201620161510.1155/2016/820890427110571
    [Google Scholar]
  71. GoscinskiM.A. NeslandJ.M. GierckskyK.E. DhakalH.P. Primary tumor vascularity in esophagus cancer. CD34 and HIF1-α expression correlate with tumor progression.Histol. Histopathol.201328101361136810.14670/hh‑28.136123653235
    [Google Scholar]
  72. VaupelP. MayerA. HöckelM. Tumor hypoxia and malignant progression.Methods Enzymol.200438133535410.1016/S0076‑6879(04)81023‑115063685
    [Google Scholar]
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