瘦素/瘦素受体相关信号通路与肿瘤的研究进展论文_胡春兰,孙晓红2通讯作者

瘦素/瘦素受体相关信号通路与肿瘤的研究进展论文_胡春兰,孙晓红2通讯作者

1.南华大学附属郴州医院 湖南郴州 423000;2.南华大学附属南华医院 湖南衡阳 421000

摘要:流行病学调查显示肥胖是多种肿瘤的形成的危险因素。肥胖,被认为是一种轻微的炎症反应过程,其特征性表现是脂肪组织高水平分泌与肿瘤发生发展相关的细胞因子如:瘦素。瘦素是一种主要由白色脂肪合成、分泌的多肽类激素,在肥胖相关肿瘤中有促炎症反应、促血管生成、扩散、迁移、凋亡等的作用。研究表明瘦素受体在多种类型肿瘤中过度表达,且与肿瘤血管生成、肿瘤细胞凋亡、炎症反应、促有丝分裂活性具有相关性。瘦素/瘦素受体主要是通过经典的信号通路Janus激酶2/信号转导和转录激活因子3(Janus Kinas2/Signal Transducers and Activators of Transcription 3,JAK2/STAT3),促分裂素原活化蛋白激酶/细胞外调节蛋白激酶1/2(Mitogen activated protein kinase/ Extracellular regulated kinase 1 and 2,MAPK/ERK1/2),磷脂酰肌醇3激酶/蛋白激酶B(Phosphoinositide 3-kinase/ Protein kinase B,PI3K/AKT)和非经典信号通路维持机体食物摄取、能量平衡、脂肪代谢、免疫反应、内分泌系统的稳定,且能在肿瘤发生、发展过程中起作用。但是,瘦素促进肿瘤发生发展的的机制善不完全清楚。本文从瘦素通过经典的JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT对肿瘤影响的研究做一综述。

关键词:瘦素;瘦素受体;JAK2/STAT3信号通路;MAPK/ERK1/2信号通路;PI3K/AKT信号通路;肿瘤

Leptin/Leptin Receptor Signaling Pathway research progress of effects on Tumors

Abstact Epidemiologic studies have suggested obesity may as a high risk factor in various cancers.Obesity is redarded as a mild inflammatory condition,its characteristic is high levels of cytokines from adipose tissue secretory related to cancers development such as:Leptin.Leptin,mainly secreted by adipose tissue,peptide hormone secretion,are involved in thses biological processes pro-inflammatory,pro-angiogenic,proliferation,migration,anti-apoptosis in obesity-related cancers.Supporting evidence overexpression of Leptin receptor(Ob-R)in various cancer,and involved in angiogenic,apoptosis,inflammatory responses,mitogenic activity.Leptin/Leptin Receptor is responsible for several canonical signaling pathways signal transduction through the activation of Janus-activated kinase 2(JAK2)/signal transducers and activatiors of transcription 3(STAT3),the mitogen-acctivated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK),phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)and non-canonical signaling pathways.Leptin-induced signals is essential to its biological effects on food intake,energy balance,adiposity,immune and endocrine systems,as well as oncogenesis.Currently,the molecules mechanisms that undelie this connection between leptin and various cancers.This review addresses the current level of understanding of canonical molecular pathways activated by leptin in various cancers.

Key Words:Leptin,Leptin Receptor,JAK2/STAT3 signalingpathway,MAPK/ERK1/2 signaling pathway,PI3K/AKT signaling pathway,Cancer

肥胖和超重人群在目前高质量生活水平条件下越来越多,世界卫生组织(WHO)报道世界上至少有4亿人口肥胖,并且预计2015年会达到7亿。研究表明,肥胖和超重会增加包括肿瘤在内的多种疾病的发病风险[1,2],至少与包括乳腺癌、宫颈癌、结直肠癌、食管癌、胆囊癌、肾癌、肝癌、卵巢癌、胰腺癌、胃癌、子宫肿瘤、多发性骨髓瘤、非-霍奇金淋巴瘤在内的13种肿瘤的发生发展相关[1-4]。肥胖人群,减低脂肪组织和炎症细胞分泌的促炎症细胞因子、趋化因子、脂肪因子如瘦素、脂联素、肿瘤坏死因子α(Tumor necrosis factor-α,TNF-α)、纤溶酶原激活物抑制因子-1(Plasminogen activator inhibitor-1,PAI-1)、白细胞介素-1(Interleukin-1,IL-1)、白细胞介素-6(Interleukin-6,IL-6)等能减低肿瘤的发生风险[5]。肥胖增加肿瘤发生风险及肥胖相关肿瘤发生的分子机制尚不完全清楚,因此,研究瘦素/瘦素受体与肿瘤相关信号通路对了解肥胖致瘤机制具有重要意义,能为肥胖人群降低肿瘤发生风险、肥胖相关肿瘤的临床治疗研究提供新思路。本文将从JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT等3条经典信号通路阐明瘦素/瘦素受体对肿瘤影响的研究。

1、瘦素/瘦素受体(Leptin/Leptin Receptor,Ob/Ob-R or LEP/LEPR)结构及功能

1.1 瘦素的结构及功能

瘦素主要由脂肪组织分泌,167个氨基酸组成的非糖基化蛋白,由Ob基因编码[6]。正常生理环境下,瘦素血液浓度约维持在5-10ng/mL,刺激中枢神经系统调节能量代谢、刺激周围神经调节糖代谢和胰岛素的分泌[7];病理生理环境下血清瘦素水平上升到50ng/mL,在促进肿瘤血管生成、凋亡抑制、侵袭、生殖、生长和免疫反应等生物学过程中起重要作用[8-12]。目前认为,瘦素能通过直接或间接诱导激活经典的JAK2/STAT3、MAPK/ERK1/2、PI3K/AKT信号通路和非经典的信号通路[13,14]调节基因转录,因此,血清瘦素水平增加,可能诱导肿瘤相关信号转导异常,促进肿瘤细胞恶性转化。

1.2 瘦素受体的结构及功能

瘦素受体(Leptin receptor,Ob-R)广泛分布全身多种组织、器官,属于细胞因子I超家族成员。细胞因子信号抑制因子(suppressor of cytokine signaling,SOCS)能结合JAK2调节Ob-Rb酪氨酸残基磷酸化[15],使血清瘦素/瘦素受体复合物维持相对稳定的水平。目前发现瘦素受体有6种[16]:Ob-Ra、Ob-Rb、Ob-Rc、Ob-Rd、Ob-Re、Ob-Rf。长型受体(Ob-RL 或 Ob-Rb)具有完整的细胞内信号转导能力,瘦素结合瘦素长型受体诱导JAK2磷酸化,使能激活PI3K/AKT和STAT3信号通路的瘦素受体第985和1138位酪氨酸磷化[17],调节肿瘤细胞生物学行为;短型受体(Ob-RS或Ob-Ra)缺乏细胞内信号区域,不能直接激活STATs途径[18,19],但是能激活JAK2、胰岛素受体底物-1(Insulin Receptor Substrates-1,IRS-1)或ERKs如MAPKs[17],影响肿瘤生物学行为。因此,正常生理条件下瘦素-瘦素受体复合物能被SOCS等负性调节系统维持在稳定水平,能有效调节食物摄入、能量代谢、脂肪代谢、胰岛素的分泌,维持体重。但在肥胖、肿瘤等病理生理环境下,致血清瘦素/瘦素受体复合物水平增加,导致病态肥胖、食欲旺盛、炎症反应、免疫异常等异常生物学过程。

综上所述,瘦素/瘦素受体能直接或间接激活JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT3等经典信号通路,调节细胞内信号转导并协同辅助因子调节基因转录,因此,血清瘦素水平的增加可能影响血管生成、凋亡抑制、侵袭、生殖、生长和免疫反应等生物学过程,提高肥胖人群的肿瘤发生危险、促进肥胖相关肿瘤的恶性进展。

2、瘦素/瘦素受体作用JAK2/STAT3信号通路对肿瘤的影响

JAK2作为JAKs家族成员,与细胞内信号转导密切相关;STATs家族成员STAT3在肿瘤的发生发展过程中起重要作用。STAT3通过JAKs磷酸化激活,形成二聚体转入细胞核,调节细胞内信号转导[20],调节多种肿瘤细胞的分化、扩散、凋亡、血管生成、增殖、免疫反应等生物学过程。瘦素和瘦素受体结合能激活JAK2,使STAT3磷酸化激活[21],磷酸化激活的STAT3能调节瘦素[22]表达,如此形成一个循环影响肿瘤细胞凋亡、血管生成、存活等生物学行为,促进肿瘤的恶性转化。大量研究证实STAT3途径与瘦素介导的多种恶性肿瘤细胞迁移[23]、扩散[24]、抗凋亡[11]、促血管生成[9]等生物学过程相关联。综上所述,瘦素/瘦素受体能通过JAK2/STAT3信号途径调节肿瘤细胞凋亡、血管生成、存活、迁移、扩散等过程。

3、瘦素/瘦素受体作用MAPK/ERK1/2信号通路对肿瘤的影响

MAPKs在很多生物学过程中起关键作用,ERK1/2是MAPKs家族成员,是Ras/Raf/MAPK级联转导信号通路的组成部分,很多学者研指出,ERK1/2能调节如细胞存活、扩散、分化、凋亡等多种生物学过程[25]。Ob-Ra或Ob-Rb能通过JAK2受体酪氨酸磷酸化以及非依赖受体磷酸化途径级联转导激活MAPKs信号途径[17,19]。在肿瘤细胞中,持续激活ERK1/ERK2在细胞周期G1过渡到S期过程中起关键作用[26],有抗凋亡并调节细胞周期作用。上述表明,瘦素/瘦素受体能通过直接或间接激活MAPK/ER1/2信号通路影响基因转录,调节多种肿瘤细胞迁移、侵袭、增殖、凋亡、血管生成。。

4、瘦素/瘦素受体作用PI3K/AKT信号通路对肿瘤的影响

PI3K构成脂质激酶家族,生长因子受体酪氨酸蛋白激酶的激活导致自身酪氨酸残基磷酸化。PI3K通过SH2结构域募集膜上磷酸化的酪氨酸残基,变构激活催化亚基,继而磷酸化激活AKT[27],其持续激活对包括乳腺癌细胞[28]、胃肠道肿瘤[29]、头颈部鳞癌[30]在内的多种肿瘤细胞的生长、扩散、活力、存活、血管生成有重要的影响。有研究证实瘦素在诱导激活PI3K/AKT信号通路过程中的重要作用,能调节乳腺癌细胞免疫反应、生长、血管生成、迁移等生物学过程[9]。由此,瘦素/瘦素受体能通过调节PI3K/AKT信号转导,调节恶性肿瘤的生物学行为。

综上所述,瘦素能作为内分泌激素,调节糖、胰岛素代谢,能作为脂肪因子调节脂肪代谢、调节体重,能作为炎症因子调节炎症反应、免疫反应,能作为促血管生成因子促肿瘤血管生成,能作为生长因子调节肿瘤细胞生长、增殖过程,并且通过调节凋亡相关基因的表达,抑制肿瘤细胞凋亡。

期刊文章分类查询,尽在期刊图书馆瘦素/瘦素受体特异性结合能通过调节与肿瘤细胞扩散、增殖、侵袭、血管生成及抗凋亡等生物学过程相关的JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT等多条信号通路促进肿瘤的恶性转化。因此,通过减低血清瘦素水平调节细胞内信号转导降低肿瘤的发生风险、抑制肿瘤的恶性转化可能成为临床抗肿瘤研究的重要思路。

小结

肿瘤是当今世界上严重威胁人类身心健康的高死亡率疾病,其发生与肿瘤微环境改变导致细胞内信号转导异常密切相关,其恶性转化与肿瘤患者临床治疗及治疗预后密切相关,但是其具体的发生、发展机制尚不完全清楚。流行病学调查研究提示肥胖是多种恶性肿瘤发生发展的高危因素。肥胖人群及肥胖相关肿瘤患者血清瘦素水平通常增高,肥胖导致肿瘤发生发展的具体机制尚不完全清楚。瘦素主要由脂肪组织分泌调节机体能量平衡、脂肪代谢、糖代谢及体重的激素,能通过JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT等多条经典信号通路,调节细胞内信号转导最终调节基因转录,诱导肿瘤细胞扩散、增殖、侵袭、血管生成、凋亡抑制等恶性转化过程。因此,降低血清瘦素水平或瘦素受体在不同组织器官的表达,能不同程度的直接或间接阻断JAK2/STAT3,MAPK/ERK1/2,PI3K/AKT等多条经典信号通路的信号转导,为临床以瘦素/瘦素受体及其相关信号通路为靶点降低肥胖人群肿瘤发生风险及抗肥胖相关肿瘤研究提供了理论依据。

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论文作者:胡春兰,孙晓红2通讯作者

论文发表刊物:《健康世界》2016年第3期

论文发表时间:2016/6/2

标签:;  ;  ;  ;  ;  ;  ;  ;  

瘦素/瘦素受体相关信号通路与肿瘤的研究进展论文_胡春兰,孙晓红2通讯作者
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