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肝细胞癌(hepatocellular carcinoma, HCC)发病率在全球范围内不断增长，超过50%的HCC患者在诊断时已是疾病晚期。聚(ADP-核糖)聚合酶1[poly(ADP-ribose) polymerases 1,PARP1]是一种普遍存在的核酶，参与多种细胞过程，包括DNA修复、凋亡、基因组稳定性和细胞分裂等。PARP1在DNA断裂修复中起重要作用，已被证明在HCC中高表达并调控HCC进展。作为HCC候选治疗靶点，PARP抑制剂(PARP inhibitors, PARPi)可与多种化疗药物协同抗HCC。本文就PARP1如何调控HCC进展及对HCC放化疗的影响进行探讨，并总结PARPi对HCC作用的分子机制，以期为HCC提供新的治疗方向。
Abstract：The incidence of hepatocellular carcinoma(HCC) is increasing worldwide, and more than 50% of HCC patients have advanced disease at the time of diagnosis. Poly(ADP-ribose) polymerases 1(PARP1) is a ubiquitous ribozyme involved in a variety of cellular processes, including DNA repair, apoptosis, genome stability and cell division. PARP1, which plays an important role in DNA break repair, has been shown to be highly expressed in HCC and regulate HCC progression. As a candidate therapeutic target for HCC, PARP inhibitors(PARPi) can synergise with a variety of chemotherapy drugs against HCC. In this review, we discussed how PARP1 regulates the progression of HCC and its effect on radiotherapy and chemotherapy, and summarized the molecular mechanism of PARPi on HCC, in order to provide a new direction for the treatment of HCC.
[1] Karpova Y,Orlicky D J,Schmidt E E,et al.Disrupting poly (ADP-ribosyl)ating pathway creates premalignant conditions in mammalian liver [J].Int J Mol Sci,2023,24(24):17205.
[2] Pazzaglia S,Pioli C.Multifaceted role of PARP-1 in DNA repair and inflammation:pathological and therapeutic implications in cancer and non-cancer diseases [J].Cells,2019,9(1):41.
[3] Rajawat J,Banerjee M.Poly(ADP-ribose) polymerase1 (PARP1) and PARP inhibitors:new frontiers in cervical cancer [J].Biochem Biophys Res Commun,2024,738:150943.
[4] Bi F F,Li D,Yang Q.Hypomethylation of ETS transcription factor binding sites and upregulation of PARP1 expression in endometrial cancer [J].Biomed Res Int,2013,2013:946268.
[5] Dziaman T,Ludwiczak H,Ciesla J M,et al.PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1 [J].PLoS One,2014,9(12):e115558.
[6] Kumar M,Jaiswal R K,Yadava P K,et al.An assessment of poly (ADP-ribose) polymerase-1 role in normal and cancer cells [J].Biofactors,2020,46(6):894-905.
[7] Paturel A,Hall J,Chemin I.Poly(ADP-ribose) polymerase inhibition as a promising approach for hepatocellular carcinoma therapy [J].Cancers,2022,14(15):3806.
[8] Shimizu S,Nomura F,Tomonaga T,et al.Expression of poly(ADP-ribose) polymerase in human hepatocellular carcinoma and analysis of biopsy specimens obtained under sonographic guidance [J].Oncol Rep,2004,12(4):821-825.
[9] Xu M,Zhao X,Zhao S,et al.Landscape analysis of lncRNAs shows that DDX11-AS1 promotes cell-cycle progression in liver cancer through the PARP1/p53 axis [J].Cancer Lett,2021,520:282-294.
[10] Zhang Y,Wu K,Liu Y,et al.UHRF2 promotes the malignancy of hepatocellular carcinoma by PARP1 mediated autophagy [J].Cell Signal,2023,109:110782.
[11] Shu Y,Jin X,Ji M,et al.Ku70 binding to YAP alters PARP1 ubiquitination to regulate genome stability and tumorigenesis [J].Cancer Res,2024,84(17):2836-2855.
[12] Chen M,Wang W,Hu S,et al.Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma [J].Cell Commun Signal,2022,20(1):39.
[13] Pan D,Yang W,Zeng Y,et al.AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma [J].Oncogene,2022,41(31):3846-3858.
[14] Wang X,Tu W,Chen D,et al.Autophagy suppresses radiation damage by activating PARP-1 and attenuating reactive oxygen species in hepatoma cells [J].Int J Radiat Biol,2019,95(8):1051-1057.
[15] Pan Q,Luo P,Shi C.PC4-mediated Ku complex PARylation facilitates NHEJ-dependent DNA damage repair [J].J Biol Chem,2023,299(8):105032.
[16] Singh M P,Cho H J,Kim J T,et al.Morin hydrate reverses cisplatin resistance by impairing PARP1/HMGB1-dependent autophagy in hepatocellular carcinoma [J].Cancers,2019,11(7):986.
[17] Pal Singh M,Pal Khaket T,Bajpai V K,et al.Morin hydrate sensitizes hepatoma cells and xenograft tumor towards cisplatin by downregulating PARP-1-HMGB1 mediated autophagy [J].Int J Mol Sci,2020,21(21):8253.
[18] Fu X L,Guo S M,Ma J Q,et al.HBXIP induces PARP1 via WTAP-mediated m(6)a modification and CEBPA-activated transcription in cisplatin resistance to hepatoma [J].Acta Pharmacol Sin,2024,45(11):2405-2419.
[19] Xia X,Wang Q,Ye T,et al.NRF2/ABCB1-mediated efflux and PARP1-mediated dampening of DNA damage contribute to doxorubicin resistance in chronic hypoxic HepG2 cells [J].Fundam Clin Pharmacol,2020,34(1):41-50.
[20] Liu H,Zhang Z,Chi X,et al.Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells [J].Sci Rep,2016,6:31009.
[21] Yang X D,Kong F E,Qi L,et al.PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma [J].Mol Cancer,2021,20(1):20.
[22] Xu X,Liu Z,Wang J,et al.Global proteomic profiling in multistep hepatocarcinogenesis and identification of PARP1 as a novel molecular marker in hepatocellular carcinoma [J].Oncotarget,2016,7(12):13730-13741.
[23] Li J,Dou D,Li P,et al.PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population [J].Tumour Biol,2017,39(7):1010428317706914.
[24] Zhang X,Wang Y,Gari A,et al.Pan-cancer analysis of PARP1 alterations as biomarkers in the prediction of immunotherapeutic effects and the association of its expression levels and immunotherapy signatures [J].Front Immunol,2021,12:721030.
[25] Guo M,Wang S M.The BRCAness landscape of cancer [J].Cells,2022,11(23):3877.
[26] Zhang J X,Li D Q,He A R,et al.Synergistic inhibition of hepatocellular carcinoma growth by cotargeting chromatin modifying enzymes and poly (ADP-ribose) polymerases [J].Hepatology,2012,55(6):1840-1851.
[27] Zai W,Chen W,Han Y,et al.Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma [J].Carcinogenesis,2020,41(3):345-357.
[28] Pocasap P,Nonpunya A,Weerapreeyakul N.Pinus kesiya Royle ex Gordon induces apoptotic cell death in hepatocellular carcinoma HepG2 cell via intrinsic pathway by PARP and Topoisomerase Ⅰ suppression [J].Biomed Pharmacother,2021,139:111628.
[29] Jia Y,Jin H,Gao L,et al.A novel lncRNA PLK4 up-regulated by talazoparib represses hepatocellular carcinoma progression by promoting YAP-mediated cell senescence [J].J Cell Mol Med,2020,24(9):5304-5316.
[30] Wang C,Tang H,Geng A,et al.Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors [J].Proc Natl Acad Sci U S A,2020,117(42):26356-26365.
[31] Lampiasi N,Umezawa K,Montalto G,et al.Poly (ADP-ribose) polymerase inhibition synergizes with the NF-κB inhibitor DHMEQ to kill hepatocellular carcinoma cells [J].Biochim Biophys Acta,2014,1843(11):2662-2673.
[32] Sun G,Miao G,Li Z,et al.Inhibition of PARP potentiates immune checkpoint therapy through miR-513/PD-L1 pathway in hepatocellular carcinoma [J].J Oncol,2022,2022:6988923.
[33] Chen G,Zheng D,Zhou Y,et al.Olaparib enhances radiation-induced systemic anti-tumor effects via activating STING-chemokine signaling in hepatocellular carcinoma [J].Cancer Lett,2024,582:216507.
[34] Gerossier L,Dubois A,Paturel A,et al.PARP inhibitors and radiation potentiate liver cell death in vitro.Do hepatocellular carcinomas have an Achilles′ heel?[J].Clin Res Hepatol Gastroenterol,2021,45(5):101553.
[35] Lai Y H,Tung K C,Chen S C.Durable response to olaparib combined low-dose cisplatin in advanced hepatocellular carcinoma with FANCA mutation:a case report [J].Medicine,2022,101(39):e30719.
[36] Funato K,Otsuka M,Sekiba K,et al.Hepatitis B virus-associated hepatocellular carcinoma with Smc5/6 complex deficiency is susceptible to PARP inhibitors [J].Biochem Biophys Res Commun,2022,607:89-95.
[37] Sun C,Jing W,Xiong G,et al.Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC [J].Cancer Lett,2022,526:180-192.
[38] Ying H,Zhang B,Cao G,et al.Role for ubiquitin-specific protease 7 (USP7) in the treatment and the immune response to hepatocellular carcinoma:potential mechanisms [J].Transl Cancer Res,2023,12(11):3016-3033.
[39] Dong Q,Du Y,Li H,et al.EGFR and c-MET cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma [J].Cancer Res,2019,79(4):819-829.
[40] Li K M,Deng L G,Xue L J,et al.AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma [J].Heliyon,2024,10(17):e36283.
[41] Cao K,Wang R,Li L,et al.Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination [J].Oncogene,2024,43(1):35-46.
[42] Wang Y,Liu X,Zuo X,et al.NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors [J].Cell Genom,2024,4(5):100550.
[43] Tong Y,Wang F,Li S,et al.Histone methyltransferase KMT5C drives liver cancer progression and directs therapeutic response to PARP inhibitors [J].Hepatology,2024,80(1):38-54.
[44] Sun L,Liu Y,Guo X,et al.Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors [J].Nat Commun,2024,15(1):5209.
[45] Bishara L A,Machour F E,Awwad S W,et al.NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition [J].DNA Repair,2021,97:103025.
基本信息:
中图分类号:R735.7
引用信息:
[1]朱玲玲,张亚妮,伍杨,等.PARP1及PARP抑制剂在肝细胞癌中的临床作用研究进展[J].胃肠病学和肝病学杂志,2026,35(03):464-468.
基金信息:
中央高校优秀青年团队培育项目(31920220065); 甘肃省卫生健康行业科研计划项目(GSWSKY2023-34;GSWSKY2022)
2026-03-18
2026-03-18