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瘦素介導(dǎo)的信號(hào)通路研究新進(jìn)展

榮小麗，楊建增,王巖*

(吉林大學(xué)中日聯(lián)誼醫(yī)院 科學(xué)研究中心,吉林 長春130033)

瘦素是由位于人類染色體(7q 31.3)ob基因編碼的一種分泌型蛋白質(zhì)通過與瘦素受體結(jié)合發(fā)揮其生理功能[1]。瘦素是能同時(shí)參與幾個(gè)系統(tǒng)的增殖和抗凋亡作用的一種多效性的荷爾蒙激素,既往研究認(rèn)為瘦素具有降低食欲減輕體重，調(diào)節(jié)脂肪沉積和能量平衡，調(diào)節(jié)神經(jīng)內(nèi)分泌作用，參與機(jī)體的免疫應(yīng)答反應(yīng)等作用。近年來研究發(fā)現(xiàn)瘦素通過介導(dǎo)細(xì)胞內(nèi)某些信號(hào)傳導(dǎo)通路發(fā)揮促進(jìn)腫瘤細(xì)胞增殖和轉(zhuǎn)移的作用。本文主要就瘦素對腫瘤細(xì)胞的影響和瘦素介導(dǎo)的信號(hào)傳導(dǎo)通路作一簡要總結(jié)。

1瘦素促進(jìn)細(xì)胞增殖

Wei Wang等[2]研究表明，瘦素能夠促進(jìn)A549(人肺腺癌細(xì)胞系)的增殖，并顯示了瘦素能夠抑制順鉑誘導(dǎo)的人類非小細(xì)胞肺癌細(xì)胞的凋亡。Nalabolu等[3]報(bào)道了在乳腺癌中瘦素和脂聯(lián)素相關(guān)性，通過體外雌激素敏感試驗(yàn)證明代謝綜合征和乳腺癌的抑癌基因具有相關(guān)性，并首次證明瘦素和脂聯(lián)素共同參與了乳腺癌的增殖過程。另外Lai等[4]人研究瘦素在非小細(xì)胞肺癌中抗凋亡機(jī)制時(shí)，發(fā)現(xiàn)瘦素通過阻斷ER受體介導(dǎo)的通路促進(jìn)了A549細(xì)胞增殖。Park研究[5]證實(shí)瘦素可以加強(qiáng)內(nèi)皮細(xì)胞COX-2 的表達(dá)，此過程是通過激活 p38有絲分裂原激酶激活蛋白和PI3K/Akt 通路引起的，進(jìn)一步通過激活具有瘦素受體依賴性的VGEFR-2進(jìn)行調(diào)節(jié)，經(jīng)瘦素處理的組織能夠增加VGEFR-2的表達(dá)，進(jìn)而促進(jìn)血管新生。Rajapurohitam實(shí)驗(yàn)也表明了[6]瘦素通過鈣神經(jīng)素通道和RhoA通路調(diào)節(jié)，能夠誘導(dǎo)的心肌細(xì)胞肥大。

2瘦素介導(dǎo)的信號(hào)通路

2.1瘦素與JAK/STAT3信號(hào)通路

Qin等[7]描述了槲皮素能夠抑制胃癌MGC-803細(xì)胞的增殖，通過JAK-STAT信號(hào)通路下調(diào)了瘦素、瘦素受體蛋白、瘦素mRNA、瘦素受體mRNA的表達(dá)。Wu等研究[8]了脂肪細(xì)胞補(bǔ)體相關(guān)蛋白(Acrp30)通過AMPK 和JAK/STAT 信號(hào)通路調(diào)節(jié)子宮內(nèi)膜癌細(xì)胞系的SPEC-2表型的改變能夠有效地逆轉(zhuǎn)瘦素誘導(dǎo)的腫瘤轉(zhuǎn)移。Li等[9]最新研究證明在惡性腎腫瘤有腎細(xì)胞caki-2細(xì)胞瘦素的促有絲分裂作用沒有影響其受體表達(dá)的改變，但是通過JAK-STAT3 和 ERK1/2信號(hào)通路交互抑制作用而引起了腫瘤細(xì)胞的增殖。Li等[10]發(fā)現(xiàn)瘦素通過激活JAK/STAT3信號(hào)通路誘導(dǎo)人髓核細(xì)胞細(xì)胞周期蛋白d1的表達(dá)和增殖，利用新的分子機(jī)制解釋了肥胖和椎間盤退行性變的密切聯(lián)系。Shang等[11]利用通過瘦素激活的JAK-STAT信號(hào)通路恢復(fù)了在低氨基酸細(xì)胞中減少的11beta-HSD2表達(dá)及活性，活化了人胎盤細(xì)胞。另外，Ladyman等[12]利用小鼠動(dòng)物模型研究了在小鼠弓狀核細(xì)胞中，注入瘦素后增加了細(xì)胞中pSTAT3的活化，在妊娠小鼠中pSTAT3比在非妊娠小鼠中明顯增高，注入瘦素導(dǎo)致了下丘腦中活化的pSTAT5減少。Wang等[13]驗(yàn)證了瘦素通過促進(jìn)人乳腺癌細(xì)胞系(MCF-7細(xì)胞)中的p-STAT3和p-AKT磷酸化，促進(jìn)了MCF-7細(xì)胞的遷移和侵襲能力，同時(shí)證明與JAK/STAT 及 PI3K/AKT信號(hào)通路上調(diào)了MMP-9 和TGF-beta的表達(dá)有關(guān)。

2.2瘦素與RhoA/LIMK1/Cofilin信號(hào)通路

LIMK1(Lim kinase1,lim激酶1)可以使絲切因子(Cofilin)磷酸化,從而逆轉(zhuǎn)Cofilin誘導(dǎo)的肌動(dòng)蛋白解聚[14]。Ratke等[15]研究瘦素誘導(dǎo)可使結(jié)腸癌細(xì)胞中LIMK1/Cofilin磷酸化水平增加，細(xì)胞遷移實(shí)驗(yàn)顯示LIMK1參與瘦素誘導(dǎo)的細(xì)胞遷移。Li等[16]在NP(Nucleus pulposus cells,髓核細(xì)胞)中瘦素通過激活RhoA/ROCK 通路能引起細(xì)胞骨架重構(gòu)，張力絲形成，LIMK1和cofilin2的磷酸化。骨關(guān)節(jié)炎(Osteoarthritis,OA)是常見的骨關(guān)節(jié)退行性變疾病之一，Liang等[17]用10 ng/ml瘦素激活OA蛋白,進(jìn)一步誘導(dǎo)RhoA-ROCK信號(hào)通路激活。實(shí)驗(yàn)結(jié)果顯示瘦素不僅能在轉(zhuǎn)錄和翻譯水平上調(diào)節(jié)LIMKI和Cofiin蛋白含量，也能直接激活OA軟骨細(xì)胞內(nèi)的LIMKI蛋白、抑制Cofilin蛋白活性。小劑量的瘦素作用于體外培養(yǎng)的OA軟骨細(xì)胞時(shí)，不會(huì)引起細(xì)胞迅速調(diào)亡。瘦素刺激OA軟骨細(xì)胞較長時(shí)間后細(xì)胞內(nèi)的F-actin表達(dá)量及熒光強(qiáng)度都明顯的增強(qiáng),.引起了細(xì)胞骨架的重排。此外，還有Harrod等[18]研究了異常的瘦素為了維持子宮肌層的收縮功能而增加了Rho激酶的表達(dá)和作用。zeidan等[19]報(bào)道,小鼠血管平滑肌細(xì)胞在瘦素刺激誘導(dǎo)之后肌動(dòng)蛋白微絲(actin)顯著增加，并且細(xì)胞明顯比原來的細(xì)胞肥大,此過程是通過細(xì)胞骨架一調(diào)節(jié)RhoA/LIMKI/Cofilin信號(hào)通路而實(shí)現(xiàn)的。

2.3瘦素與MAPK/ERK信號(hào)通路

分裂素活化蛋白激酶(mitogen-activated protein kinase,MAPK)是一組激酶，它不但能夠控制細(xì)胞的分化、增殖、和凋亡過程，還包含一些信號(hào)分子如細(xì)胞外調(diào)節(jié)蛋白激酶(extracellular regulated protein kinases,ERK)和 P38[20,21]。Will等[22]研究證明MAPK信號(hào)通道在細(xì)胞的增殖及凋亡等活動(dòng)中發(fā)揮著重要的調(diào)節(jié)作用，瘦素和脂聯(lián)素可能逆轉(zhuǎn)肌細(xì)胞的生長,與p44/42 MAPK信號(hào)和配體受體基因表達(dá)改變有關(guān)。除此之外，Chen等研究[23]瘦素誘導(dǎo)的p38 MAPK通路參與了高糖誘導(dǎo)的細(xì)胞毒性、細(xì)胞增殖、凋亡和MMP在H9c2心肌細(xì)胞中的消散。Moreira等研究表明[24]瘦素是卵母細(xì)胞成熟和卵泡發(fā)育的重要調(diào)節(jié)因子，瘦素在卵巢中通過激活MAPK通路，可能是引發(fā)卵母細(xì)胞發(fā)育的重要因素。Liang等研究[25]了瘦素在脂多糖誘導(dǎo)的胸腺細(xì)胞凋亡中的調(diào)節(jié)作用，進(jìn)一步解釋了瘦素在免疫系統(tǒng)中發(fā)揮的作用，為一些由胸腺萎縮引起的創(chuàng)傷、感染休克、器官衰竭、自身免疫病等提供了新的治療方法。

2.4瘦素與PI3K/Akt/mTOR信號(hào)通路

Beccari等發(fā)現(xiàn)[26]瘦素信號(hào)可以成為癌癥治療新的選擇方法,尤其是在過渡肥胖的患者中。Wang等[27]研究了瘦素在結(jié)腸癌中的調(diào)控作用，在108名患者中檢查了瘦素及其受體的表達(dá)情況，結(jié)果顯示瘦素及其受體的表達(dá)與T期，TNM期，淋巴結(jié)轉(zhuǎn)移和遠(yuǎn)處轉(zhuǎn)移有著緊密的聯(lián)系，并且與 p-mTOR,p-70S6 kinase,p-Akt表達(dá)正相關(guān)。說明瘦素能夠通過調(diào)節(jié)PI3K/Akt/ mTOR通路刺激HCT-116結(jié)腸癌細(xì)胞的增值和抑制其凋亡。

3結(jié)語

綜上所述，瘦素及其介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路具有促進(jìn)腫瘤細(xì)胞增殖和轉(zhuǎn)移的作用。隨著對瘦素及其介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路的深入研究，探尋其與腫瘤發(fā)生發(fā)展的內(nèi)在聯(lián)系，尋求有效的化學(xué)藥物或基因藥物抑制或切斷瘦素介導(dǎo)的信號(hào)通路，將為預(yù)防腫瘤發(fā)生和控制腫瘤發(fā)展奠定實(shí)驗(yàn)基礎(chǔ)。

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(收稿日期：2015-07-15)

作者簡介：榮小麗，女，碩士在讀，主要研究臨床檢驗(yàn)診斷學(xué)分子生物方向。

文章編號(hào)：1007-4287(2016)02-0329-03

*通訊作者

基金項(xiàng)目：國家自然科學(xué)基金30772488;國家自然科學(xué)基金81172000