分子信號(hào)通路在瘢痕疙瘩中的研究進(jìn)展

劉艷芳，吳志遠(yuǎn)

(廣東醫(yī)科大學(xué)，廣東湛江524001)

分子信號(hào)通路在瘢痕疙瘩中的研究進(jìn)展

劉艷芳，吳志遠(yuǎn)

(廣東醫(yī)科大學(xué)，廣東湛江524001)

瘢痕疙瘩(KD)是皮膚創(chuàng)傷的異常修復(fù)而產(chǎn)生的一種良性的皮膚增生性腫瘤，其病因機(jī)制尚不清楚，其治療一直是整形外科界的難題。近些年，從分子信號(hào)通路去研究瘢痕疙瘩的形成及防治方法受到廣泛關(guān)注，逐步成為瘢痕疙瘩的研究熱點(diǎn)。本文將對(duì)分子信號(hào)通路在瘢痕疙瘩發(fā)病機(jī)制及治療研究進(jìn)展做一綜述。

瘢痕疙瘩；分子信號(hào)通路；治療

KD是皮膚創(chuàng)傷后的異常修復(fù)而產(chǎn)生的一種良性的皮膚增生性腫瘤，其組織學(xué)特征為以Ⅰ、Ⅲ型膠原蛋白為主的細(xì)胞外基質(zhì)沉積，以及成纖維細(xì)胞的增殖與凋亡的失衡，表現(xiàn)為向周?chē)Ｆつw組織遷移、侵襲性生長(zhǎng)、呈瘤樣增生、難以消退及易復(fù)發(fā)等。瘢痕疙瘩的病因機(jī)制尚不清楚，是許多因素共同作用的結(jié)果。近些年，從分子信號(hào)通路去研究瘢痕疙瘩的分子機(jī)制及防治方法受到廣泛關(guān)注，逐步成為瘢痕疙瘩的研究熱點(diǎn)。本文將對(duì)分子信號(hào)通路在瘢痕疙瘩發(fā)病機(jī)制及治療研究進(jìn)展做一綜述。

1 分子信號(hào)通路與瘢痕疙瘩的形成機(jī)制

1.1 轉(zhuǎn)化生長(zhǎng)因子β1(transforming growth factor-beta1，TGF-β2)信號(hào)通路轉(zhuǎn)化生長(zhǎng)因子β是一組新近發(fā)現(xiàn)的調(diào)節(jié)許多細(xì)胞功能的生長(zhǎng)因子超家族，主要有調(diào)節(jié)細(xì)胞的增殖、凋亡、分化、遷移及ECM生成等[1]。在哺乳動(dòng)物至少發(fā)現(xiàn)有TGF-β1、TGF-β2、TGF-β3三個(gè)亞型，它們?cè)趧?chuàng)面修復(fù)中具有不同的生物學(xué)作用。TGF-β1是促纖維化的細(xì)胞因子，能夠刺激瘢痕疙瘩成纖維細(xì)胞(keloid fibroblast，KF)中膠原蛋白的生成增多，是瘢痕形成最關(guān)鍵的細(xì)胞因子[2-3]。TGF-β1發(fā)揮生物學(xué)作用需與其受體相結(jié)合從而激活信號(hào)通路。具體過(guò)程：TGF-β2首先與Ⅱ型TGF-β受體(TGF-β typeⅡreceptor，TβR-Ⅱ)結(jié)合后，使Ⅰ型TGF-β受體(TGF-βtypeⅠreceptor，TβR-Ⅰ)激活，然后在活化的受體介導(dǎo)下，使Smad2和Smad3分子磷酸化，再與Smad4結(jié)合形成異源寡聚體復(fù)合物，即Smad2/3/4復(fù)合物，然后轉(zhuǎn)位進(jìn)入核內(nèi)，與DNA結(jié)合或與其他DNA結(jié)合蛋白一起發(fā)揮轉(zhuǎn)錄因子作用，調(diào)節(jié)特異性靶基因的轉(zhuǎn)錄[4]。有研究表明smad2/3蛋白的磷酸化是激活TGF-β1/smad信號(hào)途徑的關(guān)鍵一步，Xiang等[5]發(fā)現(xiàn)肥大細(xì)胞產(chǎn)生的糜酶可以使smad2/3磷酸化從而激活TGF-β1/smad通路促進(jìn)成纖維細(xì)胞的增殖和膠原蛋白的合成。Cho等[6]發(fā)現(xiàn)抑制Smad2/3蛋白的磷酸化，可以使膠原蛋白合成降低，從而防止KD的形成。由此可見(jiàn)，TGF-β1在KD發(fā)病機(jī)制中起關(guān)鍵作用，并且可能成為防治瘢痕疙瘩形成的重要靶點(diǎn)。

1.2 絲裂原活化蛋白激酶(mitogen activated proteinkinase，MAPK)信號(hào)通路MAPK是一組能被不同的細(xì)胞外刺激而激活的一類絲氨酸/蘇氨酸蛋白激酶，可將細(xì)胞表面的刺激信號(hào)傳遞到細(xì)胞核內(nèi)部及介導(dǎo)細(xì)胞產(chǎn)生反應(yīng)的信號(hào)轉(zhuǎn)導(dǎo)通路中最為主要的一條傳遞途徑，細(xì)胞的許多生物學(xué)功能均受到MAPK信號(hào)轉(zhuǎn)導(dǎo)通路的調(diào)節(jié)。MAPK途徑主要由三個(gè)亞族組成：細(xì)胞外信號(hào)調(diào)節(jié)激酶(extracellular signal-regulatedprotein kinase，ERK)、c-Jun氨基末端激酶(c-Jun N-terminal kinase，JNK)和p38[7]。MAPK可通過(guò)介導(dǎo)TGF-β1/ Smad信號(hào)通路起作用，2010年He等[8]通過(guò)KF體外研究發(fā)現(xiàn)JNK和P38的抑制劑可以阻斷Smad2/3/4復(fù)合物的形成，從而減少PAI-1mRNA的表達(dá)，同時(shí)還誘導(dǎo)抑制性Smad蛋白Smad7的表達(dá)，減弱KF的侵襲性。

1.3 整合素與瘢痕疙瘩整合素由α和β兩個(gè)亞單位組成，哺乳動(dòng)物中目前已發(fā)現(xiàn)18種α亞基和9種β亞基，共可結(jié)合成24種不同的整合素受體。其中，α1β1、α2β1、α11β1主要結(jié)合膠原，有利于細(xì)胞增殖及分化[9]。有研究發(fā)現(xiàn)，α1β1、α2β1在KF中高表達(dá)[10]。α1β1具有促進(jìn)細(xì)胞增殖抑制膠原合成作用，而α2β1的作用卻剛好相反，并且進(jìn)一步揭示整合素的表達(dá)直接由TGF-β1調(diào)節(jié)[11-12]。Liu等[13]研究發(fā)現(xiàn)整合素中β1的缺如，會(huì)抑制TGF-β的激活，而減少膠原的生成?？梢?jiàn)整合素的表達(dá)可通過(guò)干擾TGF-β而調(diào)節(jié)KF中的ECM沉積。

1.4 哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)mTOR是細(xì)胞生長(zhǎng)和增殖的重要調(diào)節(jié)因子，mTOR是磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinases，PI3K)/蛋白激酶B(protein kinase B，Akt/PKB)信號(hào)通路的關(guān)鍵因子，主要通過(guò)磷酸化p70S6K及4E-BP兩個(gè)翻譯元件而將細(xì)胞外信號(hào)傳遞到細(xì)胞內(nèi)。mTOR是膠原蛋白的調(diào)節(jié)器，可以經(jīng)PI3K獨(dú)立調(diào)節(jié)I型膠原的表達(dá)，并在PI3K/Akt/mTOR信號(hào)途徑中調(diào)控膠原蛋白的生成和ECM沉積[14]。

1.5 Wnt與瘢痕疙瘩研究表明，Wnt信號(hào)途徑是調(diào)控細(xì)胞增殖、分化、遷移及凋亡等細(xì)胞生物活性的重要途徑[15]。Wnt與腫瘤的發(fā)生密切相關(guān)，尤其是纖維瘤病[16-17]。Igota等[18]研究發(fā)現(xiàn)Wnt家族成員Wnt5a mRNA及β-catenin水平在KF中較在正常成纖維細(xì)胞中表達(dá)增加，用重組Wnt5a多肽作用于KF，可導(dǎo)致總β-catenin水平及磷酸化GSK3-β蛋白的表達(dá)增加。這些變化提示W(wǎng)nt5a/β-catenin信號(hào)通路參與瘢痕疙瘩的形成。

2 分子信號(hào)與瘢痕疙瘩的防治

2.1 抑制TGF-β信號(hào)通路有研究提出通過(guò)抑制TGF-β信號(hào)通路的各個(gè)環(huán)節(jié)，如抑制TGF-β表達(dá)、減少KF中Ⅰ型膠原蛋白的表達(dá)及合成、抑制KF中Smads蛋白的表達(dá)等，從而達(dá)到防治瘢痕疙瘩的目的。干擾素是在不同類型細(xì)胞中具有抗增殖、抗纖維化、抗病毒的一類細(xì)胞因子。在瘢痕疙瘩的治療中干擾素可以通過(guò)調(diào)節(jié)TGF-β1的生成而影響膠原合成及成纖維細(xì)胞的增殖[19-22]。Nanda等[23]及Darougheh等[24]通過(guò)體內(nèi)外研究發(fā)現(xiàn)5-FU可以抑制成纖維細(xì)胞的增殖及TGF-β介導(dǎo)的Ⅰ型膠原蛋白的表達(dá)。5-FU也是TGF-β1/Smads信號(hào)轉(zhuǎn)導(dǎo)途徑的阻滯劑，2013年Huang等[25]發(fā)現(xiàn)5-FU和激素合用可使JNK激活，抑制TGF-β1誘導(dǎo)的Smad3/4的特異性轉(zhuǎn)錄、Smad/DNA復(fù)合物的形成及Col-1基因的轉(zhuǎn)錄，從而抑制膠原合成，有效防治了瘢痕疙瘩的形成。同年Ikeda等[26]研究發(fā)現(xiàn)，白藜蘆醇能抑制KF中Col-1、TGF-β1、αSMA的產(chǎn)生，從而抑制KF的增殖，并促進(jìn)其凋亡。他克莫司(FK-506)是一種免疫抑制劑，治療瘢痕疙瘩有多個(gè)潛在靶點(diǎn)，Wu等[27]通過(guò)體外研究證明FK-506通過(guò)下調(diào)TGF-β受體而阻斷TGF-β1/Smads信號(hào)，從而抑制KF的增殖、遷移、及膠原蛋白的生成。

2.2 抑制MAPK信號(hào)通路最新研究發(fā)現(xiàn)，F(xiàn)DA認(rèn)證的第一個(gè)口服的多激酶抑制劑索拉非尼可以阻斷KF中的MAPK/ERK信號(hào)通路，從而抑制KF的增殖、遷移、侵襲及膠原蛋白的生成，同時(shí)降低炎性細(xì)胞因子的表達(dá)及抑制血管生成，由此說(shuō)明索拉非尼在治療瘢痕疙瘩中具有潛在的應(yīng)用價(jià)值[28]。Kuo等[29-30]發(fā)現(xiàn)閃光燈脈沖激光可以激活P38以及ERK信號(hào)轉(zhuǎn)導(dǎo)途徑和阻斷活化蛋白1的轉(zhuǎn)錄使KF中TGF-β1的表達(dá)下調(diào)，從而促使KF的凋亡，使瘢痕疙瘩萎縮。

2.3 抑制mTOR信號(hào)途徑mTOR通路的抑制劑逐漸被用于瘢痕疙瘩的研究。西羅莫司又被稱為雷帕霉素，是一種大環(huán)內(nèi)脂類抗生素免疫抑制劑。研究表明，應(yīng)用西羅莫司培養(yǎng)的正常成纖維細(xì)胞及KF，隨著時(shí)間的增加，細(xì)胞中膠原蛋白及肌動(dòng)蛋白-αSMA的表達(dá)均減少[31-32]。Syed等[33]研究發(fā)現(xiàn)，一種雙重mTOR抑制劑Palomid 529通過(guò)同時(shí)抑制mTORC1和mTORC2途徑，明顯抑制瘢痕疙瘩中成纖維細(xì)胞增殖、遷移及減少ECM的形成。2014年Wong等[34]研究發(fā)現(xiàn)雷帕霉素在體內(nèi)外均能抑制ECM的沉積，也可以減少KF中Ⅰ型和Ⅲ型膠原蛋白的表達(dá)。

2.4 抑制Wnt/β-catenin、整合素信號(hào)通路2011年新加坡學(xué)者Chua等[35]研究發(fā)現(xiàn)下調(diào)KF中的分泌型卷曲相關(guān)蛋白1(SFRP1)，可以使瘢痕疙瘩對(duì)Wnt信號(hào)更敏感，從而促進(jìn)KF增殖、遷移以及ECM的合成。Wnt/β-catenin及整合素信號(hào)通路在瘢痕疙瘩的研究正處于初級(jí)階段，找出其中的關(guān)鍵靶點(diǎn)，并運(yùn)用相關(guān)抑制劑及藥物作用靶點(diǎn)而抑制瘢痕疙瘩的形成，有望為瘢痕疙瘩的防治提供新思路。

3 結(jié)語(yǔ)

瘢痕疙瘩的發(fā)病機(jī)制十分復(fù)雜，涉及諸多因素，以上信號(hào)通路在瘢痕疙瘩的形成及防治中起關(guān)鍵作用。文章雖然對(duì)近幾年來(lái)信號(hào)通路在瘢痕疙瘩的研究進(jìn)展做了一定的闡述，但對(duì)于各個(gè)信號(hào)通路引起級(jí)聯(lián)反應(yīng)的關(guān)鍵基因及各通路的相互作用還需進(jìn)一步研究。相信隨著研究的逐漸深入，瘢痕疙瘩的形成機(jī)制將越來(lái)越清楚，找出信號(hào)通路的靶點(diǎn)，研發(fā)出安全有效的藥物應(yīng)用于臨床，徹底消除廣大患者的痛苦。

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Progress of molecular signaling pathways in keloid.

LIU Yan-fang,WU Zhi-yuan.Guangdong Medical University, Zhanjiang 524001,Guangdong,CHINA

Keloids represent benign fibroproliferative tumors originating in response to the abnormal repair of trauma to the skin.However,its pathogenesis is not clear and the treatment is still a difficult problem to plastic surgery.It has been widely concerned through molecular signaling pathways to detect the formation and prevention of keloid in recent years.Also it becomes a hot topic of keloid gradually in research.This review would discuss the pathogenesis and treatment of keloid by molecular signaling pathways.

Keloid;Molecular signaling pathways;Treatment

R619+.6

A

1003—6350（2017）07—1130—03

10.3969/j.issn.1003-6350.2017.07.034

2016-07-15)

廣東省湛江市科技計(jì)劃項(xiàng)目(編號(hào)：2015A01029)

吳志遠(yuǎn)。E-mail：1608700812@qq.con