PKM2在胃腺癌中作用机制的研究进展

PKM2在胃腺癌中作用机制的研究进展

么坤

甘肃省人民医院核医学科，甘肃兰州730000

【摘要】胃腺癌是临床常见的一类病发于机体消化系统的恶性肿瘤疾病，目前关于胃腺癌发生发展的作用机制及相关的治疗靶点已成为当前医学领域研究的重点之一。丙酮酸激酶(PK)已被认定是参与细胞糖酵解的重要因子，对促进葡萄糖向丙酮酸的转变具有重要意义。M2型丙酮酸激酶(PKM2)是PK的一种亚型，也是肿瘤细胞中促进有氧糖酵解的关键酶。既往研究证实PKM2在多种恶性肿瘤疾病中发挥作用，可促进肿瘤细胞的恶性生物学行为活性，作为PK的一个亚型，是肿瘤细胞有氧糖酵解途径的一个重要调节因子。PKM2通过影响肿瘤细胞的代谢，对肿瘤的增殖、侵袭和转移发挥重要的调节作用。本文针对PKM2在胃腺癌中的相关作用机制作一综述，为后续临床靶向治疗胃腺癌提供参考。

【关键词】胃腺癌；M2型丙酮酸激酶；研究进展

Progress in the mechanism of PKM2 in gastric adenocarcinoma

MEI Kun

Nuclear Medicine Department,Gansu Provincial People's Hospital,Lanzhou, Gansu 730000,China

[Abstract]Gastric adenocarcinoma is a common disease of malignant tumors in the digestive system.At present,the mechanism of action and development of gastric adenocarcinoma have become one of the focus of research in the current medical field.Pyruvate kinase(PK)has been identified as an important factor involved in cell glycolysis and is important to promoting the transition from glucose to pyruvate.M2 type pyruvate kinase(PKM 2)is a subtype of PK and a key enzyme in promoting aerobic glycolysis in tumor cells.Previous studies confirmed that PKM 2 plays a role in various malignant tumor diseases and can promote the malignant biological behavioral activity of tumor cells.As a subtype of PK,it is an important regulator of the aerobic glycolytic pathway of tumor cells.By affecting tumor cell metabolism,PKM 2 plays an important regulatory role in tumor proliferation,invasion,and metastasis.In this paper,we reviewed the relevant mechanisms of PKM 2 in gastric adenocarcinoma to provide a reference for the subsequent clinical targeted treatment of gastric adenocarcinoma.

[Key words]Gastric adenocarcinoma;M2 pyruvate kinase

胃腺癌是临床中发病率和死亡率均较高的恶性肿瘤疾病[1]。相关研究显示胃腺癌发病早期无明显典型特征，当患者出现明显不良症状时就诊，其体内恶性肿瘤往往已处于进展期，严重影响到患者的生存质量，预后也较差[2]。需要注意的是，目前针对胃腺癌相关的有效靶向治疗方案较为单一，临床疗效与预期相比仍存在差距，探寻有效的胃腺癌分子标志物并明确相关的治疗靶点，对完善相关治疗方案和防控措施具有重要意义[3]。丙酮酸激酶（PK）是细胞实现糖酵解的重要参与因子，既往研究发现该因子在催化过程中可转化为磷酸烯醇丙酮酸（PEP），进而实现糖酵解[4]。PK在哺乳动物细胞具有四种亚型，包括PKL、PKR、PKM1和PKM2。有学者围绕恶性肿瘤相关疾病的发展机制进行研究发现，PKM2可通过增强Warburg效应从而帮助肿瘤细胞提高代谢效率

[5]。另外，PKM2可通过细胞核，对蛋白激酶相关调节基因实现转录，这一机制也提示PKM2对恶性肿瘤的生物学行为具有一定促进作用[6-7]。

2 PKM2相关概述

PK在哺乳动物细胞中由PKLR和PKM两种基因编码组成，而PKM2亚型属于PKM基因编码的重要成员[8]。需要注意的是，不同亚型在机体中的表达受组织特异性影响，PKM2大多在胚胎组织、成人正常组织及增殖活性高的细胞中广泛分布，也有研究发现其在肿瘤细胞中具有明显表达[9-10]。此前有研究发现PKM2表达情况受多因素调控[11-12]。目前绝大多数学者认为PKM2具有致癌效用，其致癌机制源于PKM2在二聚体、四聚体之间完成变构的调节，高活性四聚体PKM2对PEP的亲和力较高，可促进葡萄糖通过氧化磷酸化完全氧化分解为ATP；而低活性二聚体PKM2在多种肿瘤细胞中高表达，对PEP的亲和力较低，导致糖酵解速率低，进而引起糖酵解中间体的积累。这些中间体可参与蛋白质、核苷酸以及脂质等生物大分子的合成，有助于肿瘤细胞快速增殖[13-15]。

一项针对肿瘤微环境（TME）影响机制的研究显示，肿瘤微环境的组成离不开浸润性单核/巨噬细胞、免疫抑制细胞、成纤维细胞、脉管系统及相关的炎性因子，而这些因子也参与到肿瘤细胞的代谢过程[16-17]。近年来随着医学领域对恶性肿瘤疾病的深入研究，相关的治疗方案也呈现多元化发展，免疫治疗方案的研制及相关临床应用也使需要临床学者开始对肿瘤免疫微环境进行关注和研究[18]。目前有学者研究发现，PKM2与机体内炎性反应的发生发展间存在联系[19-21]。在肿瘤细胞的免疫代谢过程中，PKM2可通过加剧氧化磷酸化和Warburg效应促进肿瘤细胞的有效代谢[22]。另有学者研究发现，PKM2与免疫检查点程序性死亡蛋白配体-1（PD-L1）存在某种联系，PKM2对PD-L1的表达具有调控作用[23-24]。在原发性肝癌中，PKM2可通过上调PD-L1表达并降低治疗效果[25]。目前临床针对PKM2在恶性肿瘤中的作用机制相应地研制出抑制剂，并发现其抑制剂紫草素可有效对脉络膜新生血管形成和促血管生成因子的分泌产生抑制作用，分析紫草素的抑制机制发现，该抑制剂可对巨噬细胞中PKM2/STAT3/CD163的信号通路起到有效阻滞作用，进而发挥其抑制效能[26]。这一发现也为临床发掘肿瘤治疗的潜在靶点提供新的方向。

一项关于肿瘤耐药性机制的研究发现，非小细胞肺癌中关于低氧诱导的顺铂耐药性可通过外泌体PKM2作为有效途径向敏感细胞传递耐药性[27]。另有学者纳入原发性肝癌患者并取其血浆样本进行分析，发现该类患者血浆中可见外泌体PKM2表达[28]。此前已有学者研究发现原发性肝癌细胞所衍生的外泌体HCC衍生的外泌体可对肿瘤微环境实现有效调节，而外泌体PKM2亦是促成原发性肝癌进展的重要机制[29]。

3PKM2与胃腺癌的关系概述

此前有学者围绕消化系统恶性肿瘤的相关作用机制及信号通路介导等进行研究发现，PKM2与胃腺癌的发生、发展具有重要促进作用，其表达水平在一定程度上也会影响到患者预后情况[30]。Shiroki T等[31]指出，PKM2对胃腺癌细胞恶性生物学活性的提高、调控葡萄糖代谢等具有促进作用。另有国外学者围绕胃腺癌代谢机制进行分析，发现PKM2可对胃腺癌细胞相关的代谢通路进行调控，进而参与到胃腺癌的发生和进展；深入分析其作用机制发现，幽门螺旋杆菌中的细胞毒素相关基因A可对保外信号对激酶信号相关通路进行调控，而这一途径也是促进PKM2高表达的重要因素，从而加剧胃腺癌细胞的有效糖酵解效率，为胃癌细胞恶性生物学行为提供能量[32]。此前有研究证实，胃腺癌中可见PI3K/Akt/mTOR通路处于活化状态，且这一状态的持续与胃腺癌的进展息息相关[33-34]。一项针对胃癌细胞PKM2表达调控的研究显示，使用微RNA(miRNA)-let-7a对胃腺癌细胞中PKM2的表达具有显著抑制作用，当降低其表达后，胃腺癌相关肿瘤细胞的恶性生物学行为活性也明显降低[35]。有学者[36]建立耐缺氧胃癌细胞实验发现，PKM2的表达水平对具有耐缺氧的胃癌细胞增殖、侵袭等行为活性有重要影响。一项临床研究证实，胃癌中PKM2的异常高表达是促成癌细胞发生淋巴结转移、加剧预后不良风险事件发生的重要因素，提示PKM2可作为胃癌治疗的潜在靶点，有望成为评估临床预后的指标[37]。

4PKM2在临床应用中的相关概述

PKM2在多种恶性肿瘤中均呈现异常高表达，且许多研究发现PKM2与多种恶性肿瘤进展密切相关，围绕PKM2的相关治疗靶点药物的研究也具有较高的临床价值[38-39]。目前与PKM2相关的靶向药剂包括PK激活剂和抑制剂（紫草素、Benserazide），但不同学者的研究中获得的结果也存在一定差异[40-42]。有学者认为PKM2并不是恶性肿瘤发生发展的必要因素，在结直肠癌中并未发现PKM与疾病的发生进展存在密切联系

[43]。这为PKM2激活剂和抑制剂用于抗肿瘤治疗的推动具有积极意义。

5小结

PKM2作为肿瘤代谢靶点用于临床治疗还存在不少争议，PKM2在肿瘤代谢中独特的表达和调控方式决定了它将是肿瘤治疗领域的热点。随着生物学技术的进步，代谢组学、蛋白质组学、基因组学、合成生物学以及CRISPR/Cas9基因组编辑技术逐步应用于PKM2敲除细胞模型和动物模型，有助于加快PKM2的分子作用机制研究，并推动肿瘤代谢领域的发展。

参考文献

[1]孙铭博,陈水兵.胃腺癌的关键基因及通路的生物信息学分析[J].浙江医学,2022,44(20):2165-2172.

[2]陈芳,关玉峰,杨文婷,等.胃底腺型腺癌二例临床病理分析[J].海南医学,2022,33(17):2207-2211.

[3]彭小娟,寇莹,李川,等.胃腺癌乳腺转移~(18)F-FDG PET/CT显像一例[J].国际放射医学核医学杂志,2022,46(08):513-517.

[4]Isidor MS,Winther S,Markussen LK,et al.Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes[J].FEBS Lett,2020,594(7):1218-1225.

[5]Blum JE,Gheller BJ,Benvie A,et al.Pyruvate Kinase M2 Supports Muscle Progenitor Cell Proliferation but Is Dispensable for Skeletal Muscle Regeneration after Injury[J].J Nutr,2021,151(11):3313-3328.

[6]Zhang Z,Deng X,Liu Y,et al.PKM2,function and expression and regulation[J].Cell Biosci,2019,9:52.

[7]Damasceno LEA,Prado DS,Veras FP,et al.PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation[J].J Exp Med,2020,217(10):e20190613.

[8]ZHU S S,GUO Y Y,ZHANG X,et al.Pyruvate kinase M2(PKM2)in cancer and cancer therapeutics[J].Cancer Lett,2021,503:240-248.

[9]ZAHRA K,DEY T,ASHISH,et al.Pyruvate kinase M2 andcancer:the role of PKM2 in promoting tumorigenesis[J].FrontOncol,2020,10:159.

[10]CLOWER C V,CHATTERJEE D,WANG Z X,et al.Thealternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism[J].Proc Natl Acad Sci USA,2010,107(5):1894-1899.

[11]LI Y H,LI X F,LIU J T,et al.PKM2,a potential target forregulating cancer[J].Gene,2018,668:48-53.

[12]BEINAT C,PATEL C B,HAYWOOD T,et al.A clinical PETimaging tracer([18 F]DASA-23)to monitor pyruvate kinaseM2-induced glycolytic reprogramming in glioblastoma[J].Clin Cancer Res,2021,27(23):6467-6478.

[13]XIA Y,WANG X,LIU Y,et al.PKM2 is essential for bladdercancer growth and maintenance[J].Cancer Res,2022,82(4):571-585.

[14]GAO F,ZHANG X J,WANG S Y,et al.TSP50 promotes theWarburg effect and hepatocyte proliferation via regulating PKM2acetylation[J].Cell Death Dis,2021,12(6):517.

[15]LIU Y,WU H,MEI Y,et al.Clinicopathological and prognosticsignificance of PKM2 protein expression in cirrhotic hepatocellularcarcinoma and non-cirrhotic hepatocellular carcinoma[J].SciRep,2017,7(1):15294.

[16]CHEN M X,LIU H,LI Z,et al.Mechanism of PKM2 affectingcancer immunity and metabolism in Tumor Microenvironment[J].J Cancer,2021,12(12):3566-3574

[17]SUN X L,YAO L,LIANG H W,et al.Intestinal epithelialPKM2 serves as a safeguard against experimental colitis viaactivatingβ-catenin signaling[J].Mucosal Immunol,2019,12(6):1280-1290.

[18]OUYANG X X,HAN Y H,QU G J,et al.Metabolic regulation of T cell development by Sin1-mTORC2 is mediated by pyruvate kinase M2[J].J Mol Cell Biol,2019,11(2):93-106.

[19]ANGIARI S,RUNTSCH M C,SUTTON C E,et al.Pharmacological activation of pyruvate kinase M2 inhibits CD4+T cell pathogenicity and suppresses autoimmunity[J].Cell Metab,2020,31(2):391-405.

[20]HU H,TU W Z,CHEN Y G,et al.The combination of PKM2overexpression and M2 macrophages infiltration confers a poorprognosis for PDAC patients[J].J Cancer,2020,11(8):2022-2031.

[21]PALSSON-MCDERMOTT E M,DYCK L,ZASŁONA Z,et al.Pyruvate kinase M2 is required for the expression of the immunecheckpoint PD-L1 in immune cells and tumors[J].Front Immunol,2017,8:1300.

[22]LI T E,WANG S,SHEN X T,et al.PKM2 drives hepatocellular carcinoma progression by inducing immunosuppressivemicroenvironment[J].Front Immunol,2020,11:589997.

[23]XIA Q,JIA J,HU C P,et al.Tumor-associated macrophagespromote PD-L1 expression in tumor cells by regulating PKM2nuclear translocation in pancreatic ductal adenocarcinoma[J].Oncogene,2022,41(6):865-877.

[24]WANG Y,XIE L Q,ZHU M H,et al.Shikonin alleviates choroidal neovascularization by inhibiting proangiogenic factorproduction from infiltrating macrophages[J].Exp Eye Res,2021,213:108823.

[25]WANG D L,ZHAO C S,XU F,et al.Cisplatin-resistantNSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2[J].Theranostics,2021,11(6):2860-2875.DOI:10.7150/thno.51797.

[26]HOU P P,LUO L J,CHEN H Z,et al.Ectosomal PKM2 promotes HCC by inducing macrophage differentiation and remodeling the tumor microenvironment[J].Mol Cell,2020,78(6):1192-1206.

[27]DANG G H,LI T R,YANG D M,et al.T lymphocyte-derivedextracellular vesicles aggravate abdominal aortic aneurysm bypromoting macrophage lipid peroxidation and migration viapyruvate kinase muscle isozyme 2[J].Redox Biol,2022,50:102257.

[28]ALQURAISHI M,PUCKETT D L,ALANI D S,et al.Pyruvatekinase M2:a simple molecule with complex functions[J].FreeRadic Biol Med,2019,143:176-192.

[29]YANG W W,XIA Y,JI H T,et al.Nuclear PKM2 regulatesβ-catenin transactivation upon EGFR activation[J].Nature,2011,480(7375):118-122.

[30]Li H,Xu H,Xing R,et al.Pyruvate kinase M2 contributes to cell growth in gastric cancer via aerobic glycolysis[J].Pathol Res Pract,2019,215(6):152409.

[31]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 metabolis[J].Cancer Sci,2017,108(5):931-940.

[32]Ohtsu A,Ajani JA,Bai YX,et al.Everolimus for previously treated advanced gastric cancer:Results of the randomized，double-blind,phaseⅢGRANITE-1 study[J].J Clin Oncol,2013,31(31):3935-3943.

[33]Wang C,Jiang J,Ji J,et al.PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and con-tributes to the malignant development of gastric cancer[J].Sci Rep,2017,7(1):2886.

[34]Tang R,Yang C,Ma X,et al.MiR-let-7a inhibits cell prolifera-tion，migration,and invasion by down-regulating PKM2 in gastric cancer[J].Oncotarget,2016,7(5):5972-5984.

[35]Kitayama K,Yashiro M,Morisaki T,et al.Pyruvate kinase isozyme M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer[J].Cancer Sci,2017,108(12):2462-2469.

[36]Gao Y,Xu D,Yu G,et al.Overexpression of metabolic markers HK1 and PKM2 contributes to lymphatic metastasis and adverse prognosis in Chinese gastric cancer[J].Int J Clin Exp Pathol,2015,8(8):9264-9271.

[37]Wang LY,Liu YP,Chen LG,et al.Pyruvate kinase M2 plays a dual role on regulation of the EGF/EGFR signaling via E-cadherin-dependent manner in gastric cancer cells[J].PLoS One,2013,8(6):e67542.

[38]ZHOU S C,LI D,XIAO D,et al.Inhibition of PKM2 enhancessensitivity of olaparib to ovarian cancer cells and inducesDNA damage[J].Int J Biol Sci,2022,18(4):1555-1568.

[39]GRACE R F,ROSE C,LAYTON D M,et al.Safety and efficacy of mitapivat in pyruvate kinase deficiency[J].N Engl JMed,2019,381(10):933-944.

[40]ALMOUHANNA F,BLAGOJEVIC B,CAN S Z,et al.Pharmacological activation of pyruvate kinase M2 reprograms glycolysis leading to TXNIP depletion and AMPK activation in breastcancer cells[J].Cancer Metab,2021,9(1):5.

[41]ZHOU Y Y,HUANG Z N,SU J,et al.Benserazide is a novelinhibitor targeting PKM2 for melanoma treatment[J].Int JCancer,2020,147(1):139-151.

[42]LAU A N,ISRAELSEN W J,ROPER J,et al.PKM2 is notrequired for colon cancer initiated by APC loss[J].CancerMetab,2017,5:10.

[43]MORITA M,SATO T,NOMURA M,et al.PKM1 confers metabolic advantages and promotes cell-autonomous tumor cellgrowth[J].Cancer Cell,2018,33(3):355-367.

基金项目：甘肃省人民医院院内科研基金（20GSSY4-18）