謝海霞+楊曉煜
摘要:卵巢癌作為婦科惡性腫瘤之一,嚴(yán)重威脅女性的健康。卵巢癌的病因不清,近年的研究顯示脂肪酸在卵巢腫瘤細(xì)胞轉(zhuǎn)化及增殖過程中起重要作用,本文是關(guān)于該問題目前的研究進(jìn)展及可能的機(jī)制作一綜述。
關(guān)鍵詞:卵巢腫瘤;脂質(zhì)代謝;研究進(jìn)展
Abstract:Ovarian cancer as one of gynecological malignancies,a serious threat to women's health.Ovarian cancer is unclear,in recent years,studies have shown that fatty acids play an important role in the process of ovarian tumor cell transformation and proliferation.This paper is a review of the current research progress and possible mechanism of this problem.
Key words:Ovarian neoplasms;Lipid metabolism;Research progress
婦科惡性腫瘤死亡的首要原因是卵巢癌[1],其發(fā)病因素不清,但環(huán)境和內(nèi)分泌影響在卵巢癌致病因素中最受重視。根據(jù)其流行病學(xué)和病因?qū)W調(diào)查,其發(fā)病高危因素有:①環(huán)境因素:工業(yè)發(fā)達(dá)國家及上層社會婦女卵巢癌發(fā)病率高,可能與飲食中高膽固醇有關(guān)。另外,電離輻射及石棉、滑石粉會影響卵母細(xì)胞而增加誘發(fā)卵巢腫瘤的機(jī)會,吸煙及維生素A、C、E的缺乏也可能與發(fā)病有關(guān);②內(nèi)分泌因素:卵巢腫瘤多發(fā)生在未產(chǎn)婦或未生育婦,妊娠對卵巢腫瘤似有對抗作用,認(rèn)為每日排卵所致卵巢表層上皮細(xì)胞反復(fù)破損與卵巢腫瘤發(fā)生有關(guān)。在所有的高危因素中,腫瘤細(xì)胞的生長與脂肪酸密切相關(guān)。脂肪酸合成是合成代謝的能量儲存通路,近年的研究結(jié)果提示多種腫瘤細(xì)胞轉(zhuǎn)化及增殖的關(guān)鍵過程與其密切相關(guān)。脂質(zhì)是具有重要生物學(xué)功能的大分子,包括能量產(chǎn)生、信號轉(zhuǎn)導(dǎo)、細(xì)胞生長及分化,脂質(zhì)代謝紊亂與許多疾病相關(guān),其中包括冠心病、高血壓、肥胖、糖尿病。它是引起癌癥高發(fā)病率的最主要物質(zhì),特別是在乳腺癌、卵巢癌、前列腺癌。據(jù)研究,許多脂質(zhì)與卵巢癌的發(fā)生、發(fā)展有密切的聯(lián)系。比如:25-羥基膽固醇、溶血磷脂酸(LPA)、過氧化物酶體增殖物激活受體(PPAR)、血小板激活因子(PAF)、脂肪酸合酶(FAS)等。卵巢腫瘤自身脂質(zhì)介質(zhì)的異常表達(dá),以及內(nèi)分泌激素的紊亂,導(dǎo)致脂質(zhì)代謝的異常,但迄今為止,與脂代謝紊亂的關(guān)系尚不明確。本文是關(guān)于該問題目前的研究進(jìn)展及可能的機(jī)制作一綜述。
1 25-羥基膽固醇
25-羥基膽固醇是維生素D3的活性代謝形式,對人體一系列生理活動起重要的調(diào)節(jié)作用。1,25(OH)2D3的缺失會導(dǎo)致佝僂病和骨軟化,對磷酸鹽和鈣的穩(wěn)態(tài)也有重要的影響[2]。早在20世紀(jì)80年代初期,Eisman JA[3]等發(fā)現(xiàn)維生素D3分布在正常和惡性組織上,進(jìn)一步的研究發(fā)現(xiàn)1,25(OH)2D3在癌性和正常組織中有抗增殖和抗分化的作用,它是通過阻止G1期向S期的轉(zhuǎn)化來抑制正常細(xì)胞和腫瘤細(xì)胞的生長,使細(xì)胞的分化停止在G1期[5]。超生理劑量的1,25(OH)2D3和EB1089,一種1,25(OH)2D3甾體的類似物,抑制多種卵巢癌細(xì)胞株的增殖,包括OVCAR3,并減少OVCAR3在裸鼠移植小鼠上的生長[5]。1,25(OH)2D3調(diào)節(jié)一系列與卵巢癌的生長和發(fā)育相關(guān)的基因的表達(dá),比如說內(nèi)皮細(xì)胞的分化,溶血磷脂酸G蛋白偶聯(lián)受體,the CXC chemokines GRO-β,GRO-γ and IL-8[6-8]。雌激素受體α在乳腺腫瘤、卵巢腫瘤中調(diào)節(jié)基因表達(dá)及生長是由25-羥基膽固醇誘導(dǎo)的[9]。
2 溶血磷脂酸(LPA)
溶血磷脂酸是一種細(xì)胞間磷脂類信號分子,它通過G蛋白偶聯(lián)受體引起多種生物學(xué)效應(yīng)。有實(shí)驗(yàn)證實(shí),卵巢上皮性癌細(xì)胞可以產(chǎn)生LPA,LPA又可促進(jìn)卵巢癌細(xì)胞生長、黏附和轉(zhuǎn)移,并參與血管生成的調(diào)節(jié)及細(xì)胞耐藥的形成[10]。國外研究發(fā)現(xiàn)正常人血漿LPA水平很低,卵巢癌患者的腹水及血漿LPA水平顯著升高,而在其他腫瘤患者,如白血病、乳癌,血漿LPA增高不明顯[11]。LPA作用于卵巢癌細(xì)胞CAOV3后可以促進(jìn)細(xì)胞的增殖、遷移、侵襲和分泌生長因子,LPA具有促進(jìn)卵巢癌浸潤轉(zhuǎn)移的作用[12]。據(jù)文獻(xiàn),LPA通過誘導(dǎo)增殖、生長、分化的基因,包括COX-2、MMP-2等的表達(dá)促進(jìn)卵巢癌細(xì)胞的發(fā)展、進(jìn)展及代謝[13]。LPA在EC細(xì)胞的增殖和入侵中起重要的調(diào)節(jié)作用,同時(shí)具有刺激分泌uPA和MMP-7的作用[14]。LPA具有扮演自分泌、旁分泌的潛在作用,能反式激活EGF受體。EGF、LPA在OVCAR3、SKOV3人類卵巢癌細(xì)胞株中能刺激 LPA的產(chǎn)生[15]。Mandi M等研究發(fā)現(xiàn),LPA在腫瘤細(xì)胞內(nèi)環(huán)境中影響腫瘤進(jìn)展是通過粘附分子等起作用的,比如說claudin-1,同時(shí)也報(bào)道LPA在卵巢癌的表達(dá)預(yù)示不好的結(jié)局[16]。
3 過氧化物酶體增殖物激活受體(PPAR)
PPAR在許多過程中起作用,比如類固醇生成、血管生成、細(xì)胞循環(huán)、調(diào)亡、脂類代謝[17],這些過程對正常的卵巢功能起重要作用。PPAR的三種亞型,α、β、γ均在卵巢組織中表達(dá),最為顯著的是PPARγ只在顆粒細(xì)胞發(fā)展成卵子的過程中表達(dá),并且接受黃體生成素的調(diào)節(jié)。雖然從PPAR家族發(fā)現(xiàn)以來已經(jīng)對它了解許多,但關(guān)于它在卵巢組織中的作用卻知之甚少。過氧化物酶體增殖物激活受體γ是一種配體激活轉(zhuǎn)錄因子核激素受體超家族的成員,PPARγ激動劑抑制許多類型的癌癥的增長[18]。羅格列酮顯著抑制SKOV3的生存,并使其停止在G1期而誘導(dǎo)細(xì)胞凋亡,這種生長抑制是通過激活PPARγ下調(diào)c-myc mRNA和蛋白的表達(dá)起作用的[19]。Melichar B等發(fā)現(xiàn)盡管PPARγ在EOC細(xì)胞系中的表達(dá)有所不同,CDDO在所有檢測的細(xì)胞系中有相似的生長抑制作用,表明CDDO在體外的抗腫瘤作用是由PPARγ獨(dú)立的機(jī)制介導(dǎo)的[20]。
4 脂肪酸合酶
脂肪酸合酶(Fatty Acid Synthase,F(xiàn)AS)是一種多功能的復(fù)合酶,是合成脂肪酸的關(guān)鍵酶,F(xiàn)AS位于細(xì)胞胞漿內(nèi),是一種大分子蛋白復(fù)合物[21]。Kusakabe[22]等的研究結(jié)果發(fā)現(xiàn),F(xiàn)AS較高表達(dá)基本上集中分布于脂質(zhì)代謝程度高的細(xì)胞,如脂肪細(xì)胞、黃體、肝細(xì)胞等。Gormus U等發(fā)現(xiàn)Fas受體在大量組織中廣泛表達(dá),并且FasL在免疫系統(tǒng)中高度表達(dá),同時(shí)在免疫特區(qū)如眼、腦等也表達(dá)較多[23]。FasR是一種細(xì)胞表面受體,激活時(shí)觸發(fā)細(xì)胞凋亡,F(xiàn)asR在卵巢惡性上皮細(xì)胞中較良性細(xì)胞表達(dá)降低,這個(gè)表明卵巢上皮癌與Fas誘導(dǎo)的凋亡的敏感性降低可能與有關(guān)[24]。Syed V等發(fā)現(xiàn)孕酮誘導(dǎo)永生正常和惡性的卵巢表面上皮細(xì)胞的凋亡與FasL的表達(dá)增強(qiáng)有關(guān),孕酮誘導(dǎo)OVCA細(xì)胞及HOSE細(xì)胞是通過活化的Caspase-8-啟動Fas/FasL的信號轉(zhuǎn)導(dǎo)通路[25]。
綜上所述,脂質(zhì)代謝與卵巢癌的發(fā)生與發(fā)展有密切的關(guān)系,關(guān)于FAS、PPAR、LPA在腫瘤的作用機(jī)制已成為卵巢癌等惡性腫瘤的重要研究方向,卵巢癌的病因及機(jī)理不清,積極探尋脂質(zhì)代謝在卵巢腫瘤中的作用,有利于我們尋找卵巢癌的病因及發(fā)病機(jī)制,并為卵巢癌的治療找到新的突破口。
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編輯/楊倩