Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Cancer Drug Targets
  4. Volume 25, Issue 2
  5. Article
Volume 25, Issue 2
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Introduction

Lenvatinib resistance causes less than 40% of the objective response rate. Therefore, it is urgent to explore new therapeutic targets to reverse the lenvatinib resistance for HCC. HAND2-AS1 is a critical tumor suppressor gene in various cancers.

Methods

Here, we investigated the role of HAND2-AS1 in the molecular mechanism of lenvatinib resistance in HCC. It was found that HAND2-AS1 was lowly expressed in the HepG2 lenvatinib resistance (HepG2-LR) cells and HCC tissues and associated with progression-free intervals TCGA. Overexpression of HAND2-AS1 (OE-HAND2-AS1) decreased the IC of lenvatinib in HepG2-LR cells to reverse lenvatinib resistance. Moreover, OE-HAND2-AS1 induced intracellular concentrations of malondialdehyde (MDA) and lipid ROS and decreased the ratio of glutathione to glutathione disulfide (GSH/GSSG) to promote ferroptosis.

Results

A xenograft model in which nude mice were injected with OE-HAND2-AS1 HepG2-LR cells confirmed that OE-HAND2-AS1 could reverse lenvatinib resistance and decrease tumor formation . HAND2-AS1 promoted the expression of ferroptosis-related genes (TLR4, NOX2, and DUOX2) and promoted ferroptosis to reverse lenvatinib resistance by increasing TLR4/NOX2/DUOX2 competing endogenous miR-219a-1-3p in HCC cells. Besides, patients with a low HAND2-AS1 level had early recurrence after resection.

Conclusion

HAND2-AS1 promotes ferroptosis in HCC cells and reverses lenvatinib resistance by regulating TLR4/NOX2/DUOX2 axis. It suggested that HAND2-AS1 may be a potential therapeutic target and an indicator of early recurrence for HCC.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096279597240219055135
2024-03-07
2025-04-06

  • From This Site

    /content/journals/ccdt/10.2174/0115680096279597240219055135
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
     [Google Scholar]
  2. PohW. WongW. OngH. AungM.O. LimS.G. ChuaB.T. HoH.K. Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.Mol. Cancer20121111410.1186/1476‑4598‑11‑1422439738
     [Google Scholar]
  3. FornerA. ReigM. BruixJ. Hepatocellular carcinoma.Lancet2018391101271301131410.1016/S0140‑6736(18)30010‑229307467
     [Google Scholar]
  4. TanX.P. HeY. YangJ. WeiX. FanY.L. ZhangG.G. ZhuY.D. LiZ.Q. LiaoH.X. QinD.J. GuanX.Y. LiB. Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression.Signal Transduct. Target. Ther.2023811410.1038/s41392‑022‑01248‑936617552
     [Google Scholar]
  5. KudoM. FinnR.S. QinS. HanK.H. IkedaK. PiscagliaF. BaronA. ParkJ.W. HanG. JassemJ. BlancJ.F. VogelA. KomovD. EvansT.R.J. LopezC. DutcusC. GuoM. SaitoK. KraljevicS. TamaiT. RenM. ChengA.L. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial.Lancet2018391101261163117310.1016/S0140‑6736(18)30207‑129433850
     [Google Scholar]
  6. AlsinaA. KudoM. VogelA. ChengA.L. TakW.Y. RyooB.Y. EvansT.R.J. López LópezC. DanieleB. MisirS. RenM. IzumiN. QinS. FinnR.S. Effects of subsequent systemic anticancer medication following first-line lenvatinib: A post hoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma.Liver Cancer2020919310410.1159/00050462432071913
     [Google Scholar]
  7. HuB. ZouT. QinW. ShenX. SuY. LiJ. ChenY. ZhangZ. SunH. ZhengY. WangC.Q. WangZ. LiT.E. WangS. ZhuL. WangX. FuY. RenX. DongQ. QinL.X. Inhibition of EGFR overcomes acquired lenvatinib resistance driven by sTAT3–ABCB1 signaling in hepatocellular carcinoma.Cancer Res.202282203845385710.1158/0008‑5472.CAN‑21‑414036066408
     [Google Scholar]
  8. DengH. KanA. LyuN. HeM. HuangX. QiaoS. LiS. LuW. XieQ. ChenH. LaiJ. ChenQ. JiangX. LiuS. ZhangZ. ZhaoM. Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma.J. Immunother. Cancer202196e00230510.1136/jitc‑2020‑00230534168004
     [Google Scholar]
  9. GreenY.S. Ferreira dos SantosM.C. FujaD.G. ReichertE.C. CamposA.R. CowmanS.J. Acuña PilarteK. KohanJ. TrippS.R. LeiboldE.A. SirohiD. AgarwalN. LiuX. KohM.Y. ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma.Oncogene202241424709472310.1038/s41388‑022‑02460‑136097192
     [Google Scholar]
  10. LuoY. HuangS. WeiJ. ZhouH. WangW. YangJ. DengQ. WangH. FuZ. Long noncoding RNA LINC01606 protects colon cancer cells from ferroptotic cell death and promotes stemness by SCD1-Wnt/β-catenin-TFE3 feedback loop signalling.Clin. Transl. Med.2022124e75210.1002/ctm2.75235485210
     [Google Scholar]
  11. JiangX. StockwellB.R. ConradM. Ferroptosis: Mechanisms, biology and role in disease.Nat. Rev. Mol. Cell Biol.202122426628210.1038/s41580‑020‑00324‑833495651
     [Google Scholar]
  12. ZhangC. LiuX. JinS. ChenY. GuoR. Ferroptosis in cancer therapy: A novel approach to reversing drug resistance.Mol. Cancer20222114710.1186/s12943‑022‑01530‑y35151318
     [Google Scholar]
  13. ZhouN. YuanX. DuQ. ZhangZ. ShiX. BaoJ. NingY. PengL. FerrDb V2: Update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations.Nucleic Acids Res.202351D1D571D58210.1093/nar/gkac93536305834
     [Google Scholar]
  14. QuX. LiuB. WangL. LiuL. ZhaoW. LiuC. DingJ. ZhaoS. XuB. YuH. ZhangX. ChaiJ. Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer.Drug Resist. Updat.20236810093610.1016/j.drup.2023.10093636764075
     [Google Scholar]
  15. NojimaT. ProudfootN.J. Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics.Nat. Rev. Mol. Cell Biol.202223638940610.1038/s41580‑021‑00447‑635079163
     [Google Scholar]
  16. LengX. MaJ. LiuY. ShenS. YuH. ZhengJ. LiuX. LiuL. ChenJ. ZhaoL. RuanX. XueY. Mechanism of piR-DQ590027/MIR17HG regulating the permeability of glioma conditioned normal BBB.J. Exp. Clin. Cancer Res.201837124610.1186/s13046‑018‑0886‑030305135
     [Google Scholar]
  17. PengW-X. KoiralaP. MoY-Y. LncRNA-mediated regulation of cell signaling in cancer.Oncogene201736415661566710.1038/onc.2017.18428604750
     [Google Scholar]
  18. GuoM. XiaoZ.D. DaiZ. ZhuL. LeiH. DiaoL.T. XiongY. The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers.Nucleic Acids Res.20204822126181263110.1093/nar/gkaa111933275145
     [Google Scholar]
  19. GuX. ZhengQ. ChuQ. ZhuH. HAND2-AS1: A functional cancer-related long non-coding RNA.Biomed. Pharmacother.202113711131710.1016/j.biopha.2021.11131733556872
     [Google Scholar]
  20. JiangZ. LiL. HouZ. LiuW. WangH. ZhouT. LiY. ChenS. LncRNA HAND2-AS1 inhibits 5-fluorouracil resistance by modulating miR-20a/PDCD4 axis in colorectal cancer.Cell. Signal.20206610948310.1016/j.cellsig.2019.10948331760170
     [Google Scholar]
  21. LiL. LiL. HuL. LiT. XieD. LiuX. Long non-coding RNA HAND2-AS1/miR-106a/PTEN axis re-sensitizes cisplatin-resistant ovarian cells to cisplatin treatment.Mol. Med. Rep.202124576210.3892/mmr.2021.1240234476500
     [Google Scholar]
  22. SongN. LiuZ.S. XueW. BaiZ.F. WangQ.Y. DaiJ. LiuX. HuangY.J. CaiH. ZhanX.Y. HanQ.Y. WangH. ChenY. LiH.Y. LiA.L. ZhangX.M. ZhouT. LiT. NLRP3 phosphorylation is an essential priming event for inflammasome activation.Mol. Cell2017681185197.e610.1016/j.molcel.2017.08.01728943315
     [Google Scholar]
  23. VargheseF. BukhariA.B. MalhotraR. DeA. IHC Profiler: An open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples.PLoS One201495e9680110.1371/journal.pone.009680124802416
     [Google Scholar]
  24. ChouH.C. ChenC.M. Cathelicidin attenuates hyperoxia-induced lung injury by inhibiting ferroptosis in newborn rats.Antioxidants20221112240510.3390/antiox1112240536552613
     [Google Scholar]
  25. StockwellB.R. Friedmann AngeliJ.P. BayirH. BushA.I. ConradM. DixonS.J. FuldaS. GascónS. HatziosS.K. KaganV.E. NoelK. JiangX. LinkermannA. MurphyM.E. OverholtzerM. OyagiA. PagnussatG.C. ParkJ. RanQ. RosenfeldC.S. SalnikowK. TangD. TortiF.M. TortiS.V. ToyokuniS. WoerpelK.A. ZhangD.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease.Cell2017171227328510.1016/j.cell.2017.09.02128985560
     [Google Scholar]
  26. LuoX. GongH.B. GaoH.Y. WuY.P. SunW.Y. LiZ.Q. WangG. LiuB. LiangL. KuriharaH. DuanW.J. LiY.F. HeR.R. Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2.Cell Death Differ.20212861971198910.1038/s41418‑020‑00719‑233432112
     [Google Scholar]
  27. ZouY. LiH. GrahamE.T. DeikA.A. EatonJ.K. WangW. Sandoval-GomezG. ClishC.B. DoenchJ.G. SchreiberS.L. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis.Nat. Chem. Biol.202016330230910.1038/s41589‑020‑0472‑632080622
     [Google Scholar]
  28. ZhengX. WangQ. ZhouY. ZhangD. GengY. HuW. WuC. ShiY. JiangJ. N‐acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4‐acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA.Cancer Commun.202242121347136610.1002/cac2.1236336209353
     [Google Scholar]
  29. StatelloL. GuoC.J. ChenL.L. HuarteM. Gene regulation by long non-coding RNAs and its biological functions.Nat. Rev. Mol. Cell Biol.20212229611810.1038/s41580‑020‑00315‑933353982
     [Google Scholar]
  30. HuangZ.P. DingY. ChenJ. WuG. KataokaM. HuY. YangJ.H. LiuJ. DrakosS.G. SelzmanC.H. KyselovicJ. QuL.H. dos RemediosC.G. PuW.T. WangD.Z. Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy.Cardiovasc. Res.2016112254355410.1093/cvr/cvw20127557636
     [Google Scholar]
  31. YangK. ZhangW. ZhongL. XiaoY. SahooS. FassanM. ZengK. MageeP. GarofaloM. ShiL. Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer.Cell Death Differ.20233061533154910.1038/s41418‑023‑01160‑x37041291
     [Google Scholar]
  32. HuangJ. WangJ. HeH. HuangZ. WuS. ChenC. LiuW. XieL. TaoY. CongL. JiangY. Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer.Int. J. Biol. Sci.202117154493451310.7150/ijbs.6618134803512
     [Google Scholar]
  33. JingG.Y. ZhengX.Z. JiX.X. lncRNA HAND2-AS1 overexpression inhibits cancer cell proliferation in hepatocellular carcinoma by downregulating RUNX2 expression.J. Clin. Lab. Anal.2021354e2371710.1002/jcla.2371733566427
     [Google Scholar]
  34. BiH.Q. LiZ.H. ZhangH. Long noncoding RNA HAND2-AS1 reduced the viability of hepatocellular carcinoma via targeting microRNA-300/SOCS5 axis.Hepatobiliary Pancreat. Dis. Int.202019656757410.1016/j.hbpd.2020.02.01132224127
     [Google Scholar]
  35. JiangL. HeY. ShenG. NiJ. XiaZ. LiuH. CaoY. LiX. lncRNA HAND2-AS1 mediates the downregulation of ROCK2 in hepatocellular carcinoma and inhibits cancer cell proliferation, migration and invasion.Mol. Med. Rep.20202131304130910.3892/mmr.2020.1092831922232
     [Google Scholar]
  36. IsedaN. ItohS. ToshidaK. TomiyamaT. MorinagaA. ShimokawaM. ShimagakiT. WangH. KuriharaT. ToshimaT. NagaoY. HaradaN. YoshizumiT. MoriM. Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor-4 inhibition in hepatocellular carcinoma.Cancer Sci.202211372272228710.1111/cas.1537835466502
     [Google Scholar]
  37. BoW. ChenY. Lenvatinib resistance mechanism and potential ways to conquer.Front. Pharmacol.202314115399110.3389/fphar.2023.115399137153782
     [Google Scholar]
  38. ZhangQ. XiongL. WeiT. LiuQ. YanL. ChenJ. DaiL. ShiL. ZhangW. YangJ. RoesslerS. LiuL. Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma.Oncogene202342191509152310.1038/s41388‑023‑02665‑y36932115
     [Google Scholar]
  39. NevolaR. RuoccoR. CriscuoloL. VillaniA. AlfanoM. BecciaD. ImbrianiS. ClaarE. CozzolinoD. SassoF.C. MarroneA. AdinolfiL.E. RinaldiL. Predictors of early and late hepatocellular carcinoma recurrence.World J. Gastroenterol.20232981243126010.3748/wjg.v29.i8.124336925456
     [Google Scholar]
  40. WeiW. JianP.E. LiS.H. GuoZ.X. ZhangY.F. LingY.H. LinX.J. XuL. ShiM. ZhengL. ChenM.S. GuoR.P. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: A randomized clinical trial of efficacy and safety.Cancer Commun.201838111210.1186/s40880‑018‑0331‑y30305149
     [Google Scholar]
  41. MarascoG. ColecchiaA. ColliA. RavaioliF. CasazzaG. Bacchi ReggianiM.L. CucchettiA. CesconM. FestiD. Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection.J. Hepatol.201970344044810.1016/j.jhep.2018.10.02230389551
     [Google Scholar]
  42. WangQ. QiaoW. ZhangH. LiuB. LiJ. ZangC. MeiT. ZhengJ. ZhangY. Nomogram established on account of Lasso-Cox regression for predicting recurrence in patients with early-stage hepatocellular carcinoma.Front. Immunol.202213101963810.3389/fimmu.2022.101963836505501
     [Google Scholar]
  43. JiG.W. ZhuF.P. XuQ. WangK. WuM.Y. TangW.W. LiX.C. WangX.H. Radiomic features at contrast-enhanced CT predict recurrence in early stage hepatocellular carcinoma: A multi-institutional study.Radiology2020294356857910.1148/radiol.202019147031934830
     [Google Scholar]
  44. HoM.C. HasegawaK. ChenX.P. NaganoH. LeeY.J. ChauG.Y. ZhouJ. WangC.C. ChoiY.R. PoonR.T.P. KokudoN. Surgery for intermediate and advanced hepatocellular carcinoma: A consensus report from the 5th asia-pacific primary liver cancer expert meeting (APPLE 2014).Liver Cancer20165424525610.1159/00044933627781197
     [Google Scholar]
/content/journals/ccdt/10.2174/0115680096279597240219055135
Loading
HAND2-AS1 Promotes Ferroptosis to Reverse Lenvatinib Resistance in Hepatocellular Carcinoma by TLR4/NOX2/DUOX2 Axis
Curr. Cancer Drug Targets< 25, 144 (2025); https://doi.org/10.2174/0115680096279597240219055135
/content/journals/ccdt/10.2174/0115680096279597240219055135
/content/journals/ccdt/10.2174/0115680096279597240219055135
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): cancer; cells; deaths; Hepatocellular carcinoma; lenvatinib; reactive oxygen species

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test