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      Stathmin與胃腸道腫瘤關(guān)系的研究進(jìn)展

      2014-01-13 10:32劉海榮李巖
      關(guān)鍵詞:磷酸化胃腸道食管

      劉海榮+李巖

      【摘要】 Stathmin在多種惡性腫瘤細(xì)胞中都高水平表達(dá),Stathmin蛋白可以改變細(xì)胞的增殖、分化、活性等生物學(xué)行為。Stathmin的過表達(dá)可影響抗微管化學(xué)治療藥物的療效。Stathmin在胃腸道腫瘤中也有高水平表達(dá),針對(duì)Stathmin的研究對(duì)腫瘤的治療有重要的意義。

      【關(guān)鍵詞】 Stathmin; 胃腸道腫瘤

      The Study of Relationship between Stathmin and Gastrointestinal Tumor/LIU Hai-rong, LI Yan.//Medical Innovation of China,2014,11(01):154-156

      【Abstract】 Stathmin expresses high in many malignant tumor cells, The proliferation, differentiation, and other biological behavior changes of cells can be activated by stathmin protein. Overexpression of Stathmin may affect the efficacy of anti-microtubule chemotherapeutic agents. The level of stathmin expression in gastrointestinal tumors is also high, The study of stathmin has important significance for the treatment of tumors.

      【Key words】 Stathmin; Gastroenteric tumor

      First-authors address:Qianfoshan Hospital Affiliated to Shandong University, Jinan 250014, China

      doi:10.3969/j.issn.1674-4985.2014.01.073

      Stathmin是近來研究較多的微管不穩(wěn)定蛋白,在大量的組織和物種中均廣泛存在,表達(dá)于細(xì)胞質(zhì)內(nèi)。它與細(xì)胞有絲分裂紡錘體的結(jié)構(gòu)和功能關(guān)系密切。研究發(fā)現(xiàn)在神經(jīng)元細(xì)胞、再生的肝細(xì)胞、反應(yīng)性增生的淋巴結(jié)細(xì)胞等增殖細(xì)胞中Stathmin表達(dá)上調(diào)[1-2]。目前已經(jīng)證實(shí)Stathmin在白血病、肺癌、淋巴瘤、乳腺癌、前列腺癌、卵巢癌、骨肉瘤、神經(jīng)膠質(zhì)瘤及消化系統(tǒng)惡性腫瘤等多種惡性腫瘤細(xì)胞中高水平表達(dá)[3-8]。腫瘤細(xì)胞中Stathmin表達(dá)增高可降低抗微管化學(xué)治療藥物的療效。

      1 Stathmin基因

      Stathmin基因位于人染色體1p35~36.1,由5個(gè)外顯子和4個(gè)內(nèi)含子組成,基因全長6.3 kb[9]。

      2 Stathmin蛋白

      Stathmin蛋白包含149個(gè)氨基酸,共三部分構(gòu)成:N端的調(diào)節(jié)結(jié)構(gòu)域、中心區(qū)和C端的蛋白相互作用結(jié)構(gòu)域。C端功能部位可以和微管的α/β異源二聚體螯合形成T2 S三聚體復(fù)合物,調(diào)節(jié)微管蛋白的功能。中心區(qū)被蛋白水解后包含4個(gè)結(jié)構(gòu)域,其核心區(qū)域連接N端和C端,可與微管蛋白相互作用。N端由Ser16、Ser25、Ser38及Ser63四個(gè)絲氨酸磷酸化位點(diǎn)組成,它們可被鈣調(diào)蛋白依賴的蛋白激酶(camlodulin dependent protein kinase)、Cdc2蛋白激酶(Cdc 2 protein kinase)、絲裂活化蛋白激酶(mitogen activted protein kinase)、環(huán)磷酸腺苷(cyclicAMP)依賴性蛋白激酶等催化而磷酸化,對(duì)N端促使微管解聚的能力相關(guān)[10-11]。

      3 Stathmin的功能

      目前研究認(rèn)為,Stathmin通過控制細(xì)胞周期,改變細(xì)胞增殖、分化等生物學(xué)行為。同時(shí),多種細(xì)胞因子、癌基因或抑癌基因的表達(dá)產(chǎn)物,可與Stathmin相互作用,引起細(xì)胞生物學(xué)改變。如Stathmin是ASKl-p38、MAPs、PAK、cdc等細(xì)胞內(nèi)激酶的作用底物,其下游的作用靶點(diǎn)是在細(xì)胞分裂中起重要作用的微管、微管蛋白、紡錘體等細(xì)胞器。在轉(zhuǎn)錄水平上還可受到p53和E2F的調(diào)節(jié)[12-15],Stathmin的這種功能被學(xué)術(shù)界稱為信號(hào)轉(zhuǎn)導(dǎo)中繼站。

      3.1 控制細(xì)胞周期和影響細(xì)胞增殖 Cassimeris[16]發(fā)現(xiàn)Stathmin通過增加“災(zāi)難”微管的發(fā)生從而促使微管解聚,抑制Stathmin可導(dǎo)致微管聚合的增加。Rubin等[9]研究證實(shí)Stathmin表達(dá)減少的細(xì)胞中微管聚合增加,而Stathmin表達(dá)增多的細(xì)胞中微管聚合減少。Stathmin突變時(shí),Stathmin不能磷酸化,微管不能形成有功能的紡錘體。目前多項(xiàng)研究結(jié)果表明,Stathmin的主要作用是促使微管解聚和(或)阻止微管蛋白異二聚體的聚合,使已聚合的微管不穩(wěn)定。Stathmin的促微管解聚功能受自身磷酸化水平的調(diào)節(jié),當(dāng)Stathmin磷酸化水平顯著降低時(shí),微管聚合,細(xì)胞周期被阻滯于G1/S期。當(dāng)Stathmin的磷酸化靶點(diǎn)突變時(shí),細(xì)胞周期被阻滯于G2/M期,紡錘體難以形成,染色體分離受阻[17]。但是目前Stathmin誘導(dǎo)微管不穩(wěn)定的機(jī)制目前還有爭論[18-20]。

      3.2 改變細(xì)胞增殖和分化 在正常人體組織中,Stathmin表達(dá)水平在具有較高細(xì)胞代謝能力的組織中高,而在較低增殖能力的組織中表達(dá)較低。在卵巢癌、肺癌等腫瘤中也發(fā)現(xiàn)高增殖的腫瘤細(xì)胞中Stathmin表達(dá)水平明顯高于低增殖的腫瘤細(xì)胞[1]。Hanash等[2]在HL60白血病細(xì)胞中發(fā)現(xiàn)Stathmin表達(dá)明顯增高,當(dāng)細(xì)胞被誘導(dǎo)發(fā)生分化和細(xì)胞增殖明顯減慢時(shí),細(xì)胞中Stathmin表達(dá)水平降低。在其他幾個(gè)白血病細(xì)胞系中也發(fā)現(xiàn)細(xì)胞增殖停滯并分化較好時(shí),Stathmin表達(dá)水平降低。Guo等[21]發(fā)現(xiàn),大鼠骨骺干細(xì)胞內(nèi)Stathmin表達(dá)水平高時(shí),細(xì)胞增殖;Stathmin表達(dá)被抑制時(shí),細(xì)胞增殖減弱,并且發(fā)生細(xì)胞分化。endprint

      4 Stathmin與胃腸道腫瘤的關(guān)系

      研究證實(shí)Stathmin蛋白在多種惡性腫瘤中有異常高表達(dá),目前已經(jīng)證實(shí)有高表達(dá)的腫瘤有前列腺癌、頭頸部腫瘤、乳腺癌、肺癌、卵巢癌、白血病、骨肉瘤等。胃腸道惡性腫瘤與Stathmin的相關(guān)性研究目前國內(nèi)外較少。

      Jeon等[22]觀察到Stathmin蛋白的表達(dá)與胃癌的腫瘤的分化程度、淋巴結(jié)轉(zhuǎn)移程度、浸潤深度和TNM分期有關(guān);Stathmin蛋白陽性表達(dá)的胃癌患者無復(fù)發(fā)中位生存期明顯低于表達(dá)陰性的患者,用siRNA技術(shù)在SNV16等胃癌細(xì)胞系敲除Stathmin后發(fā)現(xiàn)細(xì)胞的增殖、移行及浸潤受到明顯抑制。王峰等[23]應(yīng)用免疫組化及原位雜交方法研究了3株食管鱗癌細(xì)胞系、食管鱗癌組織、癌旁不典型增生組織和正常食管黏膜組織中Stathmin mRNA和蛋白的表達(dá),發(fā)現(xiàn)3株食管鱗癌細(xì)胞系中Stathmin mRNA和蛋白均呈高表達(dá)。與食管鱗癌的分化程度、淋巴結(jié)轉(zhuǎn)移、腫瘤浸潤深度及TNM分期顯著相關(guān),食管鱗癌組織中Stathmin mRNA及蛋白的陽性表達(dá)較癌旁不典型增生組織及正常食管黏膜組織明顯增高。王瀟等[24]用免疫組化方法檢測Stathmin在31例食管癌組織中表達(dá),發(fā)現(xiàn)Stathmin蛋白的高水平表達(dá)與食管鱗狀細(xì)胞癌的浸潤深度、TNM分期和淋巴結(jié)轉(zhuǎn)移顯著相關(guān)。

      Hsieh等[25]采用免疫印記方法檢測肝癌細(xì)胞中的Stathmin蛋白表達(dá),發(fā)現(xiàn)肝癌細(xì)胞中Stathmin蛋白的高表達(dá)與局部浸潤、早期復(fù)發(fā)及不良預(yù)后相關(guān)。他們應(yīng)用特定的siRNA在沉默Stathmin基因,發(fā)現(xiàn)胃癌和肝癌細(xì)胞的增殖、浸潤、轉(zhuǎn)移能力受到抑制。Ogino等[26]采用免疫組化法檢測結(jié)直腸癌患者中Stathmin蛋白的表達(dá),發(fā)現(xiàn)54%表達(dá)陽性。同時(shí)研究Stathmin與多種因素(包括肥胖、腫瘤分期、β-catenin、cyclin D1、p53等)與死亡率的關(guān)系,結(jié)果發(fā)現(xiàn)肥胖患者Stathmin蛋白的高表達(dá)與死亡率增加相關(guān),他認(rèn)為Stathmin蛋白的作用與患者自身體質(zhì)密切相關(guān)。吳民華等[27]發(fā)現(xiàn)大腸癌中Stathmin蛋白表達(dá)明顯高于大腸腺瘤,提示Stathmin的高表達(dá)也可能通過促進(jìn)細(xì)胞增殖,在大腸腺瘤進(jìn)展為大腸癌中發(fā)揮了一定作用。Stathmin蛋白過表達(dá)與大腸癌的發(fā)生密切相關(guān),但不能作為判斷大腸癌惡性程度的指標(biāo)。Wang等[28]通過觀察肝癌細(xì)胞中Stathmin的表達(dá)發(fā)現(xiàn),p27通過抑制Stathmin阻止其與微管的分離從而干擾細(xì)胞間期微管功能,上調(diào)p27在肝癌細(xì)胞中的表達(dá)可抑制Stathmin蛋白促肝癌細(xì)胞分裂與增殖功能。Jiang等[29]發(fā)現(xiàn)下調(diào)Stathmin所需的轉(zhuǎn)化生長因子,可以靶向抑制胰腺癌細(xì)胞的生長。

      總之,目前研究已經(jīng)發(fā)現(xiàn)Stathmin在多種胃腸道腫瘤的發(fā)生、發(fā)展中發(fā)揮著重要的作用,包括食管癌、胃癌、腸癌、肝癌、胰腺癌。但研究數(shù)目較少,需要展開更多針對(duì)胃腸道腫瘤與Stathmin表達(dá)的研究,同時(shí)隨著研究的深入,針對(duì)抑制Stathmin在腫瘤細(xì)胞中的表達(dá)的研究可以改善腫瘤的預(yù)后及提高腫瘤對(duì)化療藥物的敏感性,為腫瘤的治療開辟新的思路。

      參考文獻(xiàn)

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      [5] Mistry S J, Atweh G F. Therapeutic interactions between stathmin inhibit ion and chemotherapeutic agents in prostate cancer[J]. Mol Cancer Ther,2006,5(12):3248-3257.

      [6] Xu S G, Yan P J, Shao Z M. Differential proteomic analysis of ahighlyme tastatic variant of human breast cancer cells using two dimensional differential gelelectrophoresis[J]. J Cancer Res Clin Onco,2010,136(10):1545-1556.endprint

      [7] Gan L, Guo K, Li Y, et al. Up-regulated expression of stathmin may be associated with hepatocarcinogenesis[J]. Oncol Rep,2010,23(4):1037-1043.

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      [12] Mizumura K, Takeda K, Hashimoto S, et al. Identification of Opl8/Stathmin as a potential target of ASKI-p38 MAP kinase cascade[J]. J Cell Physiol,2006,206(2):363.

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      [16] Cassimeris L. The oncoprotein 18/Stathmin family of microtubule destabilizers[J]. Curr Opin Cell Biol,2002,14(1):18-24.

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      [18] Belmont L D, Mitehimn T J. Identification 0f a protein that interacts with tubulin dimers and increases the catastropherate of micrombules[J]. J Cell,1996,84(4):623.

      [19] Howell B, Larsson N, Gullberg M, et al. Dissociation of the tubulin-sequestering and microtubule catastrophe-promoting activities of oncoproteinl8/Stathmin[J]. J Mol Bid Cell,1999,10(6):105.

      [20] Jourdain L, Curmi P, Sobel A, et al. Stathmin: a tubulin-sequesteringprotein which forms a ternary T2S complex with two tubulin molecules[J]. J Biochem,1997,36(36):10 817-10 821.

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      (收稿日期:2013-06-04) (本文編輯:王宇)endprint

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