乳酸脱氢酶在胃癌诊治中的研究进展

doi:10.11904/j.issn.1002-3070.2024.03.009

摘要/Abstract

摘要： 我国是世界第一胃癌大国,胃癌发病率及死亡率在我国的各种恶性肿瘤中均居第三。研究发现肿瘤细胞有自身的能量代谢特点,即使在氧气充足的情况下,肿瘤细胞也更倾向于利用糖酵解产生能量,又称为“有氧糖酵解”。有氧糖酵解可导致乳酸增加,促进肿瘤细胞的增殖及侵袭,而驱动这种现象的关键酶是乳酸脱氢酶(Lactate dehydrogenase,LDH)。在胃癌患者中LDH水平显著升高,并且LDH可在许多方面促进胃癌的发生发展。本文将论述LDH在肿瘤糖酵解中的作用、与胃癌的相关性及临床应用价值,并讨论LDH在胃癌靶向治疗中的研究进展。

关键词: 肿瘤糖酵解, 乳酸脱氢酶, 胃癌预后, 胃癌预测模型

Abstract: China is the rank 1st of gastric cancer in the world,and the incidence and mortality of gastric cancer rank the 3rd among various malignant tumors in China.It has been found that tumor cells have their own energy metabolism characteristics.Even in the presence of sufficient oxygen,tumor cells are more inclined to use glycolysis to produce energy,also known as “aerobic glycolysis”.Aerobic glycolysis can lead to an increase in lactate,promoting the acceleration of tumor cell proliferation and invasiveness,and the key enzyme driving this phenomenon is lactate dehydrogenase (LDH).LDH levels are significantly elevated in patients with gastric cancer,and LDH can contribute to the occurrence and development of gastric cancer in many ways.This article will discuss the role of LDH in tumor glycolysis,which is correlated with gastric cancer as well as its clinical application value.It will also discuss the research progress of LDH in targeted therapy for gastric cancer.

Key words: Tumor glycolysis, Lactate dehydrogenase, Prognosis of gastric cancer, Prediction model of gastric cancer

中图分类号:

R735.2

廖俊, 李春峰, 薛英威, 祖洪亮. 乳酸脱氢酶在胃癌诊治中的研究进展[J]. 实用肿瘤学杂志, 2024, 38(3): 200-206.

LIAO Jun, LI Chunfeng, XUE Yingwei, ZU Hongliang. Research progress of lactate dehydrogenase in the diagnosis and treatment of gastric cancer[J]. Journal of Practical Oncology, 2024, 38(3): 200-206.

参考文献

1 Maomao C,He L,Dianqin S,et al.Current cancer burden in China:epidemiology,etiology,and prevention[J].Cancer Biol Med,2022,19(8):1121-1138.
2 Fukushi A,Kim HD,Chang YC,et al.Revisited metabolic control and reprogramming cancers by means of the Warburg effect in tumor cells[J].Int J Mol Sci,2022,23(17):10037.
3 Abdel-Wahab AF,Mahmoud W,Al-Harizy RM.Targeting glucose metabolism to suppress cancer progression:prospective of anti-glycolytic cancer therapy[J].Pharmacol Res,2019,150:104511.
4 Koukourakis MI,Giatromanolaki A.Warburg effect,lactate dehydrogenase,and radio/chemo-therapy efficacy[J].Int J Radiat Biol,2019,95(4):408-426.
5 Kocianova E,Piatrikova V,Golias T.Revisiting the Warburg effect with focus on lactate[J].Cancers (Basel),2022,14(24):6028.
6 Khan AA,Allemailem KS,Alhumaydhi FA,et al.The biochemical and clinical perspectives of lactate dehydrogenase:an enzyme of active metabolism[J].Endocr Metab Immune Disord Drug Targets,2020,20(6):855-868.
7 Goldberg E,Eddy EM,Duan C,et al.LDHC:the ultimate testis-specific gene[J].J Androl,2010,31(1):86-94.
8 Zhang Y,Zhang T,Zhao Y,et al.Lactate dehydrogenase D serves as a novel biomarker for prognosis and immune infiltration in lung adenocarcinoma[J].BMC Cancer,2023,23(1):759.
9 Semenza GL,Jiang BH,Leung SW,et al.Hypoxia response elements in the aldolase A,enolase 1,and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1[J].J Biol Chem,1996,271(51):32529-32537.
10 Shim H,Dolde C,Lewis BC,et al.c-Myc transactivation of LDH-A:implications for tumor metabolism and growth[J].Proc Natl Acad Sci U S A,1997,94(13):6658-6663.
11 Shi M,Cui J,Du J,et al.A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer[J].Clin Cancer Res,2014,20(16):4370-4380.
12 Jiang W,Zhou F,Li N,et al.FOXM1-LDHA signaling promoted gastric cancer glycolytic phenotype and progression[J].Int J Clin Exp Pathol,2015,8(6):6756-6763.
13 Okada K,Fujiwara Y,Takahashi T,et al.Overexpression of forkhead box M1 transcription factor (FOXM1)is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer[J].Ann Surg Oncol,2013,20(3):1035-1043.
14 Hu S,Jiang Q,Luo D,et al.miR-200b is a key regulator of tumor progression and metabolism targeting lactate dehydrogenase A in human malignant glioma[J].Oncotarget,2016,7(30):48423-48431.
15 Jin L,Chun J,Pan C,et al.Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis[J].Oncogene,2017,36(27):3797-3806.
16 Shao M,Zhang J,Zhang J,et al.SALL4 promotes gastric cancer progression via hexokinase II mediated glycolysis[J].Cancer Cell Int,2020,20:188.
17 Jiang Z,Wang X,Li J,et al.Aldolase A as a prognostic factor and mediator of progression via inducing epithelial-mesenchymal transition in gastric cancer[J].J Cell Mol Med,2018,22(9):4377-4386.
18 Yang T,Shu X,Zhang HW,et al.Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis[J].Cell Death Dis,2020,11(10):870.
19 Shiroki T,Yokoyama M,Tanuma N,et al.Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism[J].Cancer Sci,2017,108(5):931-940.
20 Barron CC,Bilan PJ,Tsakiridis T,et al.Facilitative glucose transporters:implications for cancer detection,prognosis and treatment[J].Metabolism,2016,65(2):124-139.
21 Liu X,Zou X,Zhou Y,et al.LDHA and LDHB overexpression promoted the Warburg effect in malignantly transformed GES-1 cells induced by N-nitroso compounds[J].Food Chem Toxicol,2023,180:114007.
22 Jin S,Yin E,Feng C,et al.Regulating tumor glycometabolism and the immune microenvironment by inhibiting lactate dehydrogenase with platinum(iv)complexes[J].Chem Sci,2023,14(31):8327-8837.
23 Chen X,Liu L,Kang S,et al.The lactate dehydrogenase (LDH)isoenzyme spectrum enables optimally controlling T cell glycolysis and differentiation[J].Sci Adv,2023,9(12):eadd9554.
24 Sharma D,Singh M,Rani R.Role of LDH in tumor glycolysis:regulation of LDHA by small molecules for cancer therapeutics[J].Semin Cancer Biol,2022,87:184-195.
25 Zhang Y,Lin S,Chen Y,et al.LDH-Apromotes epithelial-mesenchymal transition by upregulating ZEB2 in intestinal-type gastric cancer[J].Onco Targets Ther,2018,11:2363-2373.
26 Ping W,Senyan H,Li G,et al.Increased lactate in gastric cancer tumor-infiltrating lymphocytes is related to impaired T cell function due to miR-34a deregulated lactate dehydrogenase a[J].Cell Physiol Biochem,2018,49(2):828-836.
27 Jin HF,Wang JF,Shao M,et al.Down-regulation of miR-7 in gastric cancer is associated with elevated LDH-A expression and chemoresistance to Cisplatin[J].Front Cell Dev Biol,2020,8:555937.
28 Wang XH,Jiang ZH,Yang HM,et al.Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression[J].Clin Transl Med,2021,11(1):e279.
29 Han ZR,Jiang XL,Fan WC.LAMC1 is related to the poor prognosis of patients with gastric cancer and facilitates cancer cell malignancies[J].Neoplasma,2021,68(4):711-718.
30 Zhu W,Ma L,Qian J,et al.The molecular mechanism and clinical significance of LDHA in HER2-mediated progression of gastric cancer[J].Am J Transl Res,2018,10(7):2055-2067.
31 da Silva EL,Mesquita FP,Aragão DR,et al.Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death[J].Toxicol Appl Pharmacol,2023,475:116630.
32 Augoff K,Hryniewicz-Jankowska A,Tabola R.Lactate dehydrogenase 5:an old friend and a new hope in the war on cancer[J].Cancer Lett,2015,358(1):1-7.
33 Chen WS,Huang ZX,Zhang HH,et al.Lactate dehydrogenase and risk of readmission with gastric cancer:a propensity score matching analysis[J].J Invest Surg,2023,36(1):2172488.
34 Kostakis ID,Vaiopoulos AG,Philippou A,et al.Preoperative serum lactate dehydrogenase levels in colorectal and gastric cancer:a hospital-based case-control study[J].Biomark Med,2013,7(1):131-137.
35 Comandatore A,Franczak M,Smolenski RT,et al.Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers[J].Semin Cancer Biol,2022,86(Pt 2):93-100.
36 Zhao LJ,Liu FX,Wang XP,et al.Analysis of clinical prognosis of 68 patients with gastric mucosa-associated lymphoid tissue lymphoma[J].Zhonghua Yi Xue Za Zhi,2020,100(32):2511-2517.
37 Wu Z,Liu D,Deng F.The role of vitamin D in immune system and inflammatory bowel disease[J].J Inflamm Res,2022,15:3167-3185.
38 Zhou Q,Lan X,Li N,et al.Analysis of prognostic factors and design of prognosis model for patients with stage IV gastric cancer following first-line palliative chemotherapy[J].Cancer Manag Res,2020,12:10461-10468.
39 Ruzzo A,Graziano F,Bagaloni I,et al.Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab[J].Gastric Cancer,2020,23(6):1064-1074.
40 Hao LS,Liu Q,Tian C,et al.Correlation and expression analysis of hypoxia-inducible factor 1α,glucose transporter 1 and lactate dehydrogenase 5 in human gastric cancer[J].Oncol Lett,2019,18(2):1431-1441.
41 Chen J,Zou X.Prognostic significance of lactate dehydrogenase and its impact on the outcomes of gastric cancer:a systematic review and meta-analysis[J].Front Oncol,2023,13:1247444.
42 Wang ZX,Yang LP,Qiu MZ,et al.Prognostic value of preoperative serum lactate dehydrogenase levels for resectable gastric cancer and prognostic nomograms[J].Oncotarget,2016,7(26):39945-39956.
43 Namikawa T,Ishida N,Tsuda S,et al.Prognostic significance of serum alkaline phosphatase and lactate dehydrogenase levels in patients with unresectable advanced gastric cancer[J].Gastric Cancer,2019,22(4):684-691.
44 Xie Z,Zhou H,Wang L,et al.The Significance of the preoperative lactate dehydrogenase/albumin ratio in the prognosis of colon cancer:a retrospective study[J].PeerJ,2022,10:e13091.
45 Chen Q,Li GL,Zhu HQ,et al.The neutrophil-to-lymphocyte ratio and lactate dehydrogenase combined in predicting liver metastasis and prognosis of colorectal cancer[J].Front Med (Lausanne),2023,10:1205897.
46 Peng RR,Liang ZG,Chen KH,et al.Nomogram based on lactate dehydrogenase-to-albumin ratio (LAR)and platelet-to-lymphocyte ratio (PLR)for predicting survival in nasopharyngeal carcinoma[J].J Inflamm Res,2021,14:4019-4033.
47 Aday U,Tatli F,Akpulat FV,et al.Prognostic significance of pretreatment serum lactate dehydrogenase-to-albumin ratio in gastric cancer[J].Contemp Oncol (Pozn),2020,24(3):145-149.
48 Makley LN,Gestwicki JE.Expanding the number of ′druggable′ targets:non-enzymes and protein-protein interactions[J].Chem Biol Drug Des,2013,81(1):22-32.
49 Conners R,Schambach F,Read J,et al.Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase[J].Mol Biochem Parasitol,2005,142(2):137-148.
50 Le A,Cooper CR,Gouw AM,et al.Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression[J].Proc Natl Acad Sci U S A,2010,107(5):2037-2042.
51 Liu R,Wang X,Shen Y,et al.Long non-coding RNA-based glycolysis-targeted cancer therapy:feasibility,progression and limitations[J].Mol Biol Rep,2021,48(3):2713-2727.
52 Yang WQ,Zhang Y.RNAi-mediated gene silencing in cancer therapy[J].Expert Opin Biol Ther,2012,12(11):1495-1504.
53 Manjunath LE,Singh A,Som S,et al.Mammalian proteome expansion by stop codon readthrough[J].Wiley Interdiscip Rev RNA,2023,14(2):e1739.
54 Aldosari BN,Alfagih IM,Almurshedi AS.Lipid nanoparticles as delivery systems for RNA-based vaccines[J].Pharmaceutics,2021,13(2):206.
55 D′Andrea F,Vagelli G,Granchi C,et al.Synthesis and biological evaluation of bew glycoconjugated LDH inhibitors as anticancer agents[J].Molecules,2019,24(19):3520.
56 Li Petri G,El Hassouni B,Sciarrillo R,et al.Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter,and preclinical activity of new anti-LDH-A compounds[J].Br J Cancer,2020,123(4):644-656.
57 Giovannetti E,Leon LG,Gómez VE,et al.A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells,and modulated the expression of the human equilibrative transporter-1[J].Nucleosides Nucleotides Nucleic Acids,2016,35(10-12):643-651.
58 Zhao Z,Han F,Yang S,et al.Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells:involvement of the Akt-mTOR signaling pathway[J].Cancer Lett,2015,358(1):17-26.
59 Yang Y,Chong Y,Chen M,et al.Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer:from bedside to bench[J].J Transl Med,2021,19(1):170.
60 Kooshki L,Mahdavi P,Fakhri S,et al.Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products:a promising strategy in combating cancer[J].BioFactors,2022,48(2):359-383.
61 Song S,Chen Q,Li Y,et al.Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma[J].Gut,2021,70(12):2238-2248.
62 Oshima N,Ishida R,Kishimoto S,et al.Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy[J].Cell Rep,2020,30(6):1798-1810.
63 Han JH,Lee EJ,Park W,et al.Natural compounds as lactate dehydrogenase inhibitors:potential therapeutics for lactate dehydrogenase inhibitors-related diseases[J].Front Pharmacol,2023,14:1275000.
64 Akbari B,Baghaei-Yazdi N,Bahmaie M,et al.The role of plant-derived natural antioxidants in reduction of oxidative stress[J].Biofactors,2022,48(3):611-633.
65 Han JH,Kim M,Kim HJ,et al.Targeting lactate dehydrogenase A with catechin resensitizes SNU620/5FU gastric cancer cells to 5-Fluorouracil[J].Int J Mol Sci,2021,22(10):5406.
66 Zhao M,Wei F,Sun G,et al.Natural compounds targeting glycolysis as promising therapeutics for gastric cancer:a review[J].Front Pharmacol,2022,13:1004383.